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|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
PMC11276725_p3
|
PMC11276725
|
sec[0]/p[3]
|
Introduction
| 3.904297 |
biomedical
|
Study
|
[
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0.154541015625
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[
0.5869140625,
0.0204620361328125,
0.392333984375,
0.0003421306610107422
] |
Supported by Barlow’s theory, Kenny highlights three subtypes of MPA: (i) MPA as focal anxiety, in which there is no generalized social anxiety; (ii) MPA that co-occurs alongside with other manifestations of social anxiety; and (iii) MPA that co-occurs with panic and depression. These perspectives suggest that MPA may be linked to an intersection between the individual’s developmental history (which may be more or less impactful in the case of focal MPA and more severe in the third subtype) and specific psychosocial conditions (such as performance requirements, technical and musical preparation, public exposure or competitiveness). Acknowledging this intersection, several researchers have recommended preventive health programs for musicians, designed to increase the quality of musical performance and students’ health and well-being. Nonetheless, according to research , an understanding of the context of the performance situation (e.g., playing solo or in a group, the performance environment, competition) is required to recognize and prevent MPA. Hence, the development of reliable psychometric instruments can contribute to identify contextual specificities of MPA.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p4
|
PMC11276725
|
sec[0]/sec[0]/p[0]
|
Psychometric instruments of MPA
| 2.271484 |
biomedical
|
Study
|
[
0.923828125,
0.0007944107055664062,
0.0751953125
] |
[
0.76611328125,
0.130615234375,
0.1024169921875,
0.0008883476257324219
] |
Several studies have applied and/or developed and validated inventories and scales to understand, identify and confirm hypotheses associated with MPA, as regards behavioral, cognitive, and physiological responses. However, none of the instruments presented below analyze or evaluate the context of the performance situation, consequently limiting the understanding of MPA in varied contexts.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p5
|
PMC11276725
|
sec[0]/sec[0]/p[1]
|
Psychometric instruments of MPA
| 3.435547 |
other
|
Other
|
[
0.25927734375,
0.0010223388671875,
0.73974609375
] |
[
0.314453125,
0.361572265625,
0.3232421875,
0.0008988380432128906
] |
The inventories commonly used in studies addressing MPA include: (i) the Music Performance Anxiety Scale : 55 items addressing adaptive and maladaptive anxiety, MPA, cognitive and emotional components; (ii) the Music Performance Anxiety Questionnaire : 32 items concerning coping with anxiety, judgmental thoughts about performance, worrying about the impact of anxiety on performance, and concerns with the reaction of others, oneself and the audience; (iii) the Performance Anxiety Questionnaire : 20 items related to cognitive and somatic feelings and two additional qualitative items about coping strategies and performance anxiety feelings; (iv) the Kenny Music Performance Anxiety Inventory : 40 items regarding proximal somatic anxiety and worries about performance, worry/dread (negative cognitions) focused on self/other scrutiny, depression/hopelessness (psychological vulnerability), parental empathy, memory, generational transmission of anxiety, anxious apprehension and biological vulnerability; (v) the Performance Anxiety Scale for Music Students : 24 items associated with MPA, such as fear of stage, avoidance and symptoms; (vi) the Music Performance Anxiety Scale : 58 items about causes/situational factors, temporal occurrence, cognitive, affective, behavioral and somatic manifestations, and autonomic arousal; and (vii) the Mazzarolo Music Performance Anxiety Scale : 5 items to measure the global frequency and intensity of MPA episodes and their negative impact (aversion to future music performances).
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p6
|
PMC11276725
|
sec[0]/sec[0]/p[2]
|
Psychometric instruments of MPA
| 2.203125 |
biomedical
|
Study
|
[
0.57177734375,
0.0007333755493164062,
0.427734375
] |
[
0.880859375,
0.1151123046875,
0.003490447998046875,
0.0003962516784667969
] |
Among the instruments presented above, the K-MPAI, which presents good psychometric properties, has been broadly translated and validated for other languages, including Continental Portuguese and Brazilian Portuguese , with a Cronbach’s alpha coefficient of α = 0.91 and α = 0.957, respectively. The four factors and 30 items of the Continental Portuguese version were extracted through an exploratory factor analysis. Nevertheless, it was not developed and designed for the Portuguese context.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p7
|
PMC11276725
|
sec[0]/sec[0]/p[3]
|
Psychometric instruments of MPA
| 1.402344 |
other
|
Study
|
[
0.0194091796875,
0.0003662109375,
0.98046875
] |
[
0.552734375,
0.440673828125,
0.005512237548828125,
0.0013227462768554688
] |
It is noteworthy that Trigo , in his research on the translation and validation of the MPAI-A into Portuguese – an inventory designed for samples of adolescent music students developed by Osborne and Kenny , detected weaknesses concerning the principal component analysis (scale items), requiring further research. This weakness may be associated with problems in adapting this inventory to Portuguese. A scale validation study for other languages is relevant but does not take into account a contextual understanding of the specific environment . Thus, there is currently no specific MPA assessment tool developed for the context of higher music education in Portugal, which suggests a significant research gap.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276725_p8
|
PMC11276725
|
sec[0]/sec[0]/p[4]
|
Psychometric instruments of MPA
| 2.740234 |
other
|
Study
|
[
0.19384765625,
0.000835418701171875,
0.80517578125
] |
[
0.9951171875,
0.004184722900390625,
0.00038886070251464844,
0.00015401840209960938
] |
This research aimed to determine if the Portuguese Music Performance Anxiety Scale (PoMPAS) – in Portuguese: “Escala Portuguesa de Avaliação da Ansiedade na Performance Musical (EPAAPM)” – is a valid and reliable measure for the context of higher music education in Portugal, based on theoretical models that highlight behavioral, cognitive, and physiological dimensions. In this study, we aimed to add and evaluate the contextual factor of the performance situation, such as the formalities associated with performance, or the contexts of competitions or orchestral auditions, and the physiological symptoms experienced before and during the performance.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276725_p9
|
PMC11276725
|
sec[0]/sec[0]/p[5]
|
Psychometric instruments of MPA
| 1.649414 |
other
|
Study
|
[
0.05487060546875,
0.00045299530029296875,
0.94482421875
] |
[
0.80078125,
0.197021484375,
0.0013484954833984375,
0.0007653236389160156
] |
The research question that supports this research is: Can an inventory specifically designed for the Portuguese context adequately assess the impact of MPA in Portuguese higher music education? To answer this question, the research involved designing a scale for this context that assesses the behavioral, cognitive, and physiological responses, adding items that can also measure the impact of the performance situation and its associated physiological dimensions.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p10
|
PMC11276725
|
sec[1]/sec[0]/p[0]
|
Participants and sample characteristics
| 1.301758 |
other
|
Study
|
[
0.04278564453125,
0.0006394386291503906,
0.95654296875
] |
[
0.736328125,
0.2607421875,
0.00165557861328125,
0.0011806488037109375
] |
Seven hundred and three students from public and private higher education institutions (universities and polytechnic schools) participated in this study. Participants were invited through institutional emails, personally by the first author of this research, and via social networks such as Instagram, Facebook, and WhatsApp, in order to reach a wide and diverse range of participants and institutions.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276725_p11
|
PMC11276725
|
sec[1]/sec[0]/p[1]
|
Participants and sample characteristics
| 1.344727 |
other
|
Study
|
[
0.0247039794921875,
0.000492095947265625,
0.974609375
] |
[
0.576171875,
0.42138671875,
0.0014562606811523438,
0.0011119842529296875
] |
The criteria for participation in this study were: (1) being enrolled in a higher education institution in Portugal and currently attending bachelor, master or PhD courses, and (2) answering all the items in both questionnaires. The higher education system in Portugal includes two main types of institutions: universities and polytechnic institutes. The universities can offer bachelor, master and PhD courses, while the polytechnic institutes usually offer only bachelor and master courses.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p12
|
PMC11276725
|
sec[1]/sec[0]/p[2]
|
Participants and sample characteristics
| 1.892578 |
biomedical
|
Study
|
[
0.8583984375,
0.0016736984252929688,
0.139892578125
] |
[
0.9814453125,
0.017974853515625,
0.0003209114074707031,
0.00027823448181152344
] |
Although 703 students participated, we only considered valid the fully answered questionnaires. Thus, the total sample was N = 414 ( Table 1 ). Of these, 166 were male (40.1%), 245 were female (59.2%), and three did not want to identify their gender (0.7%).
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11276725_p13
|
PMC11276725
|
sec[1]/sec[0]/p[3]
|
Participants and sample characteristics
| 2.408203 |
biomedical
|
Study
|
[
0.9619140625,
0.0011005401611328125,
0.0367431640625
] |
[
0.9921875,
0.00753021240234375,
0.00024819374084472656,
0.00014150142669677734
] |
The ages ranged from 18 to 60 ( M = 23.78; SD = 6.46). We established a priori the need for a sample with an absolute minimum of 400, as it simultaneously agreed with Comrey and Lee’s guidelines and Nunnally’s criterion of a subject-to-item ratio of 10:1 (at least 10 participants per item).
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276725_p14
|
PMC11276725
|
sec[1]/sec[1]/p[0]
|
Procedure
| 1.606445 |
biomedical
|
Study
|
[
0.94970703125,
0.0028839111328125,
0.0472412109375
] |
[
0.89501953125,
0.1004638671875,
0.0029163360595703125,
0.0015096664428710938
] |
Two instruments were developed for this study.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276725_p15
|
PMC11276725
|
sec[1]/sec[1]/sec[0]/p[0]
|
Sociodemographic questionnaire
| 1.736328 |
biomedical
|
Study
|
[
0.931640625,
0.00217437744140625,
0.06610107421875
] |
[
0.96142578125,
0.037353515625,
0.0008187294006347656,
0.000537872314453125
] |
A sociodemographic questionnaire was created to collect participant data ( Table 1 ) such as age, gender, institution, graduation, and instrument.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p16
|
PMC11276725
|
sec[1]/sec[1]/sec[1]/p[0]
|
Portuguese music performance anxiety scale
| 2.255859 |
other
|
Study
|
[
0.42626953125,
0.0011224746704101562,
0.57275390625
] |
[
0.994140625,
0.0053253173828125,
0.0002803802490234375,
0.00012636184692382812
] |
Prior to developing the PoMPAS, we conducted a qualitative study , which supported the formulation of the initial questions (bank of items) associated with the context of Portuguese higher education music students, identifying latent MPA-related perceptions about symptoms and contextual factors. Thus, we planned, a priori , a scale with four main factors: (1) behavioral/emotional, (2) cognitive, (3) physiological/somatic, and (4) the context of the performance situation (new factor). In addition, some of the K-MPAI’s items were adapted as models for strengthening the creation of the bank of items of the new scale.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p17
|
PMC11276725
|
sec[1]/sec[1]/sec[1]/p[1]
|
Portuguese music performance anxiety scale
| 1.500977 |
other
|
Other
|
[
0.10662841796875,
0.00101470947265625,
0.892578125
] |
[
0.457763671875,
0.537109375,
0.003387451171875,
0.0014972686767578125
] |
Separate sessions of thinking-aloud discussion, with music students (eight), music researchers (two) and psychology researchers (two), following Van Someren et al. , were undertaken to verify the semantic content and assessing its appropriateness.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276725_p18
|
PMC11276725
|
sec[1]/sec[1]/sec[1]/p[2]
|
Portuguese music performance anxiety scale
| 1.716797 |
biomedical
|
Study
|
[
0.75732421875,
0.002040863037109375,
0.2408447265625
] |
[
0.60888671875,
0.388427734375,
0.002017974853515625,
0.00093841552734375
] |
The preliminary version of the PoMPAS included 40 items. A Likert scale with five response options was used, with scores from 1 (I completely disagree) to 5 (I completely agree).
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p19
|
PMC11276725
|
sec[1]/sec[1]/sec[1]/p[3]
|
Portuguese music performance anxiety scale
| 1.204102 |
other
|
Other
|
[
0.379150390625,
0.0023021697998046875,
0.61865234375
] |
[
0.021026611328125,
0.97802734375,
0.0005965232849121094,
0.00046706199645996094
] |
The sociodemographic questionnaire and the scale were available online via the LimeSurvey interface at https://forms.ua.pt/ , from December 2021 to September 2022, with the ID 488167.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276725_p20
|
PMC11276725
|
sec[1]/sec[1]/sec[2]/p[0]
|
Ethical consideration
| 1.279297 |
biomedical
|
Other
|
[
0.68115234375,
0.0033702850341796875,
0.3154296875
] |
[
0.02862548828125,
0.97021484375,
0.0005927085876464844,
0.0006546974182128906
] |
We provided an informed consent form to each participant, informing about the purpose of the study and that they could withdraw at any time and without any consequences, and that all responses would be confidential and anonymous. This research furthermore complied with the General Data Protection Regulation (GDPR) of the European Union and was approved by the Ethics and Deontology Board of University of Aveiro .
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p21
|
PMC11276725
|
sec[1]/sec[2]/p[0]
|
Data analysis
| 3.529297 |
biomedical
|
Study
|
[
0.99609375,
0.0003495216369628906,
0.003482818603515625
] |
[
0.99951171875,
0.00039649009704589844,
0.00012874603271484375,
0.00004279613494873047
] |
Descriptive analysis was undertaken to describe the participants’ sociodemographic characteristics (mean, frequency and percentages – Table 1 ). To analyze the factor structure of the PoMPAS, a psychometric study was carried out through exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). The Solomon method was used to split the total sample into equivalent subsamples for exploratory and confirmatory factor analysis .
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276725_p22
|
PMC11276725
|
sec[1]/sec[2]/sec[0]/p[0]
|
Exploratory factor analysis
| 4.113281 |
biomedical
|
Study
|
[
0.998046875,
0.0003108978271484375,
0.001628875732421875
] |
[
0.99951171875,
0.0002751350402832031,
0.0003490447998046875,
0.0000324249267578125
] |
The sample adequacy and factorability were assessed using the Sample Adequacy Index: Kaiser-Meyer-Olkin (KMO - > 0.70) and the significance of Bartlett’s test of sphericity. The extraction method used was Weighted Least Squares Mean and Variance Adjusted (RDWLS) with oblique rotation using Robust Promin . To determine the most appropriate number of factors, Parallel Analysis techniques with random permutation of observed data were employed . Standardized factor loadings ≥0.30 were considered relevant for item retention in the model. After each item exclusion, a new factor analysis was conducted following the same procedures until the structure contained only items with factor loadings above the established threshold (≥ 0.30). The stability of factors was assessed using the H index . The H index evaluates how well a set of items represents a common factor . H values range from 0 to 1. High H values (> 0.80) suggest a well-defined latent variable that is more likely to be stable across different studies. Low H values suggest a poorly defined latent variable that is likely to be unstable across different studies .
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p23
|
PMC11276725
|
sec[1]/sec[2]/sec[1]/p[0]
|
Confirmatory factor analysis
| 4.015625 |
biomedical
|
Study
|
[
0.96142578125,
0.0004646778106689453,
0.038299560546875
] |
[
0.9853515625,
0.0138092041015625,
0.0005621910095214844,
0.00006824731826782227
] |
The Diagonally Weighted Least Squares (DWLS) estimator with robust standard error calculation was used due to the ordinal nature of the Likert scale measurement . The adequacy of the estimated model was evaluated using the chi-square ( χ2 ), degrees of freedom ( df ), and the χ2/df ratio, along with fit indices such as Root Mean Square Error of Approximation (RMSEA), Comparative Fit Index (CFI), Tucker-Lewis Index (TLI), and Standard Root Mean Square Residual (SRMR). The χ2/df ratio should be less than five or preferably less than three, RMSEA values should be less than 0.08, and CFI and TLI values should preferably be >0.95. The Standard Root Mean Square Residual (SRMR) should be <0.08 .
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276725_p24
|
PMC11276725
|
sec[1]/sec[2]/sec[1]/p[1]
|
Confirmatory factor analysis
| 3.972656 |
biomedical
|
Study
|
[
0.986328125,
0.00033283233642578125,
0.013519287109375
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[
0.99853515625,
0.001018524169921875,
0.00037741661071777344,
0.000033020973205566406
] |
Internal consistency was assessed using Cronbach’s Alpha and McDonald’s Omega. Additionally, as evidence of score accuracy, the Average Variance Extracted (AVE) was calculated as a measure of the amount of variance captured by a construct relative to the amount of variance due to measurement error. Cronbach’s alpha and McDonald’s omega were calculated for Exploratory and Confirmatory analysis. Values ≥0.70 were considered adequate.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p25
|
PMC11276725
|
sec[1]/sec[2]/sec[1]/p[2]
|
Confirmatory factor analysis
| 2.5 |
biomedical
|
Study
|
[
0.97021484375,
0.0005636215209960938,
0.0293426513671875
] |
[
0.87158203125,
0.1265869140625,
0.0015106201171875,
0.0004336833953857422
] |
Exploratory Factor Analyses were conducted using FACTOR software version 12.04.05 . Confirmatory Factor Analyses and internal consistency analysis, via Cronbach’s Alpha and McDonald’s Omega, were performed using JASP software (version 0.18.03).
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276725_p26
|
PMC11276725
|
sec[2]/sec[0]/p[0]
|
Exploratory factor analysis
| 2.417969 |
biomedical
|
Study
|
[
0.951171875,
0.00133514404296875,
0.04742431640625
] |
[
0.99755859375,
0.0019121170043945312,
0.00027370452880859375,
0.0001016855239868164
] |
An exploratory factor analysis was carried out on the preliminary 40-item PoMPAS. Regarding the sample, a ratio of five respondents per estimated item was obtained . The dataset was initially analyzed to detect inconsistent values related to participants’ responses to the instrument’s items. No inconsistencies or missing data were detected. Table 2 provides a univariate descriptive analysis for the 40 items of the PoMPAS.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p27
|
PMC11276725
|
sec[2]/sec[0]/p[1]
|
Exploratory factor analysis
| 4.214844 |
biomedical
|
Study
|
[
0.99853515625,
0.0003879070281982422,
0.0010480880737304688
] |
[
0.99951171875,
0.00019073486328125,
0.00023412704467773438,
0.00005072355270385742
] |
The average scores at the scale levels ranged from 1.88 to 4.15. The skewness and kurtosis of the items showed values within the limits, as per the perspective proposed by Kline . The EFA process began by conducting Bartlett’s sphericity test , which was significant, and the Kaiser-Meyer-Olkin (KMO) measure (KMO = 0.90), which was deemed adequate according to the literature . Subsequently, permutation-based parallel analysis was applied, showing the retention of three factors. Therefore, EFA was performed with the number of factors fixed at three. Following the EFA execution, items #1, #2, #16, #18, #20, #21, #22, #28, #35, #39, #40 were excluded for having factor loadings below 0.30 or cross-loadings with the difference less than 0.20. Although item #26 (“During a performance, I feel an increase in muscle tension”) was statistically recommended (0.521), its grouping was loaded onto factor 1. However, this item would have made more sense if it had been grouped into factor 2 due to its theoretical similarity to item #25 (“Before a performance, I feel an increase in muscle tension”). Thus, we decided to exclude item #26. The remaining items achieved factor loadings above the recommended threshold (> 0.30), all factors were theoretically significant and plausible , presenting a cumulative variance proportion of 52.64%. The 28-item model with three factors exhibited satisfactory fit indices ( χ2 = 478.050, df = 322; χ2/df = 1.48; CFI = 0.99; TLI = 0.98; RMSEA = 0.04). Table 3 presents the factorial model of the PoMPAS.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p28
|
PMC11276725
|
sec[2]/sec[0]/p[2]
|
Exploratory factor analysis
| 4.101563 |
biomedical
|
Study
|
[
0.9951171875,
0.00021719932556152344,
0.004547119140625
] |
[
0.99951171875,
0.0003681182861328125,
0.0002646446228027344,
0.000028371810913085938
] |
We defined the three factors as: Behavioral/emotional factor (BEF – F1) composed of 13 items; Contextual/physiological factor (CPF – F2) composed of 11 items, and Cognitive factor (CF – F3) composed of 5 items. The measure of replicability of the factorial structure indicates that Factor 1 f(H-Observed: 0.96), Factor 2 (H-Observed: 0.93), and Factor 3 (H-Observed: 0.95) were above the recommended threshold. The three factors showed satisfactory indices (Factor 1: α = 0.91, CI 95%[0.90–0.93]; ω = 0.92, CI 95%[0.90–0.93]; Factor 2: α = 0.87, CI 95%[0.84–0.89]; ω = 0.88, CI 95%[0.85–0.90]; Factor 3: α = 0.84, CI 95%[0.81–0.87]; ω = 0.84, CI 95%[0.81–0.88]).
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11276725_p29
|
PMC11276725
|
sec[2]/sec[1]/p[0]
|
Confirmatory factor analysis
| 4.136719 |
biomedical
|
Study
|
[
0.98193359375,
0.00045299530029296875,
0.017486572265625
] |
[
0.99951171875,
0.00038170814514160156,
0.0002486705780029297,
0.00003504753112792969
] |
The three-factor model showed adequate fit measures ( χ2 = 866.39; df = 347; p < 0.001; χ2/df = 2.49; TLI = 0.98; CFI = 0.98; RMSEA = 0.09 CI 90% [0.08–0.09]); however, item #38 (“Even in contexts that cause me anxiety, I believe I will achieve a good performance”) presented a negative and low factorial load. In this sense, it was decided to exclude and check the fit indices as well as the factor loading of the remaining items. After excluding item #38, maintaining the factorial configuration, the model showed adequate fit measures ( χ2 = 870.23; df = 347; p < 0.001; χ2/df = 2.50; TLI = 0.98; CFI = 0.98; RMSEA = 0.09 CI 90% [0.08–0.09]), all items were statistically significant and loaded above 0.50. The CFA model was organized in the following manner: A Behavioral/Emotional Factor (BEF - F1) comprising of 12 items, a Contextual/Physiological Factor (CPF - F2) comprising of 10 items, and a Cognitive Factor (CF - F3) comprising of 5 items (as listed in Table 4 ), making a total of 27 items.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p30
|
PMC11276725
|
sec[2]/sec[1]/p[1]
|
Confirmatory factor analysis
| 4.007813 |
biomedical
|
Study
|
[
0.978515625,
0.00033354759216308594,
0.02099609375
] |
[
0.99951171875,
0.0004184246063232422,
0.000278472900390625,
0.00002473592758178711
] |
It is worth mentioning that most correlations between items and factors proved to be strong (0.34 to 0.64). Each dimension evidenced an acceptable internal consistency (Factor 1: α = 0.90, CI 95%[0.88–0.92]; ω = 0.90, CI 95%[0.88–0.92]; Factor 2: α = 0.88, CI 95%[0.85–0.90]; ω = 0.88, CI 95%[0.86–0.91]; Factor 3: α = 0.81, CI 95%[0.77–0.85]; ω = 0.81, CI 95%[0.77–0.85]), demonstrating good reliability. The values of the AVE (Average Variance Extracted) were adequate (Factor 1: 0.52; Factor 2: 0.52; Factor 3: 0.62).
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p31
|
PMC11276725
|
sec[3]/p[0]
|
Discussion
| 1.59668 |
other
|
Study
|
[
0.039703369140625,
0.0005183219909667969,
0.9599609375
] |
[
0.96044921875,
0.0382080078125,
0.0006861686706542969,
0.0005021095275878906
] |
This research aimed to determine if the Portuguese Music Performance Anxiety Scale (PoMPAS) – in Portuguese: “Escala Portuguesa de Avaliação da Ansiedade na Performance Musical (EPAAPM)” – is a valid and reliable measure for the context of higher music education in Portugal.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.714283 |
PMC11276725_p32
|
PMC11276725
|
sec[3]/p[1]
|
Discussion
| 4 |
biomedical
|
Study
|
[
0.9794921875,
0.00036525726318359375,
0.0200958251953125
] |
[
0.9990234375,
0.0005354881286621094,
0.0002377033233642578,
0.000028967857360839844
] |
The interpretation process began by conducting EFA with the number of factors identified, as well as assessing the KMO and Bartlett’s sphericity indices . Current guidelines with recommendations for conducting EFA describe the superior performance of parallel analysis in ordinal data compared to other factor extraction techniques . Therefore, for the current study, we opted to use Parallel Analysis, which indicated the extraction of two factors. In this sense, we tested the structure regarding the feasibility of three factors. Considering both the conceptual relationship of the items and the factor loading in each obtained factor, the three-factor model has good psychometric properties.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p33
|
PMC11276725
|
sec[3]/p[2]
|
Discussion
| 3.521484 |
biomedical
|
Study
|
[
0.966796875,
0.0003981590270996094,
0.03289794921875
] |
[
0.99755859375,
0.0017843246459960938,
0.0006437301635742188,
0.000060439109802246094
] |
In this exploratory model, Factor 1 captured the construct related to behavioral/emotional, while Factor 2 referred to contextual/physiological, and Factor 3 related to cognitive. The three factors were well-defined and exhibited high replicability [Factor 1: (H-Observed: 0.96), Factor 2: (H-Observed: 0.93), Factor 3: (H-Observed: 0.95)]. Additionally, the exploratory model demonstrated a good fit based on satisfactory fit indices.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p34
|
PMC11276725
|
sec[3]/p[3]
|
Discussion
| 4.140625 |
biomedical
|
Study
|
[
0.99853515625,
0.0003707408905029297,
0.0012493133544921875
] |
[
0.99951171875,
0.00021147727966308594,
0.0003399848937988281,
0.00004464387893676758
] |
Following the exploratory factor analysis (EFA) outlined previously, a confirmatory factor analysis (CFA) was conducted to further validate the factorial structure of the PoMPAS. The CFA aimed to confirm the fit of the three-factor model (BEF – F1, CPF – F2, and CF – F3), as identified in the EFA. After excluding item #38, the confirmatory factor analysis showed adequate fit indices in the multifactorial solution of three first-order factors. Furthermore, the CFA demonstrated that a model with three dimensions was justified in theory and practice. It is worth mentioning that, in a complex model (i.e., with various parameters to be estimated), the χ2 result was not considered as a criterion for discarding the model . The reliability, assessed using both Cronbach’s alpha and McDonald’s omega, was satisfactory across exploratory and confirmatory analyses. Notably, McDonald’s omega is highlighted as a preferred index over Cronbach’s alpha due to its consideration of the individual importance of each item within the construct, as determined by their factor loadings .
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p35
|
PMC11276725
|
sec[3]/p[4]
|
Discussion
| 3.927734 |
biomedical
|
Review
|
[
0.56298828125,
0.001560211181640625,
0.435302734375
] |
[
0.30810546875,
0.060699462890625,
0.630859375,
0.0005898475646972656
] |
Comparing the PoMPAS with the seven MPA scales described above highlights both similarities and differences. While the PoMPAS assesses behavioral/emotional, contextual/physiological, and cognitive dimensions associated with MPA, the MPAS measures MPA through cognitive and emotional components, seeking to understand adaptive and maladaptive anxiety. The MPAQ emphasizes coping strategies, judgmental attitudes/thoughts about performance, concern about the impact of anxiety and worry about the reaction of others, oneself and the audience. Fehm and Schmidt’s PAQ, on the other hand, assesses cognitive and somatic feelings and seeks to understand feelings of performance anxiety and coping strategies. The K-MPAI assesses proximal somatic anxiety and performance worries, negative cognitions, psychological vulnerability, parental empathy, memory, generational transmission of anxiety, apprehension and biological vulnerability. The PASMS measures stage fright, avoidance and symptoms of MPA. The MPAS evaluates the frequency and intensity of situational factors, occurrence, and cognitive, affective, behavioral and somatic manifestations. The M-MPAS assesses MPA’s global frequency and intensity and the negative impact on future music performances.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p36
|
PMC11276725
|
sec[3]/p[5]
|
Discussion
| 1.091797 |
other
|
Other
|
[
0.01125335693359375,
0.0004248619079589844,
0.98828125
] |
[
0.159423828125,
0.8359375,
0.00330352783203125,
0.001495361328125
] |
After checking the differences between the scales, we can verify that each has specific assets for measuring MPA. However, none of the instruments shown takes into account the context of the performance situation, a crucial factor that limits the understanding of MPA, particularly in higher education, the primary focus of this research.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p37
|
PMC11276725
|
sec[3]/p[6]
|
Discussion
| 2.441406 |
biomedical
|
Study
|
[
0.76904296875,
0.0007600784301757812,
0.2301025390625
] |
[
0.97802734375,
0.0178680419921875,
0.0036792755126953125,
0.00024437904357910156
] |
Authors such as Papageorgi et al. , Zarza et al. , and Casanova et al. have highlighted the influence of the performance situation context on MPA levels. This factor, which is often overlooked, is a key strength of this study. By addressing this influence, the study not only enhances our understanding of MPA but also contributes to the development of more effective MPA measurement tools.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p38
|
PMC11276725
|
sec[3]/p[7]
|
Discussion
| 1.699219 |
other
|
Other
|
[
0.037353515625,
0.00047135353088378906,
0.96240234375
] |
[
0.0670166015625,
0.92724609375,
0.00518035888671875,
0.00074005126953125
] |
The PoMPAS is designed to understand, confirm, and identify the global characteristics of students’ MPA in that context. Moreover, the PoMPAS scale stands out due to its emphasis on assessing MPA “before” and “during” performance, setting it apart from other scales. This perspective has been mentioned by music students in the Portuguese context , highlighting that the psychophysiological sensations of MPA are predominantly experienced “before” and “during” (and to a lesser extent, “after”) the performance. This insight opens avenues for developing tailored strategies to alleviate MPA in these specific moments, while considering the unique profile of each student. The PoMPAS may have a positive impact in this field since it broadens the understanding and assessment of MPA and, consequently, addresses limitations of other scales.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p39
|
PMC11276725
|
sec[3]/p[8]
|
Discussion
| 1.876953 |
other
|
Other
|
[
0.405029296875,
0.0020847320556640625,
0.5927734375
] |
[
0.0222015380859375,
0.9482421875,
0.029022216796875,
0.0005826950073242188
] |
According to Rocha Zaidhaft and Ortega , the cultural context has become increasingly relevant for health actions. Kirmayer highlights that cultural contexts are diverse, encompassing not only spatial but also temporal and historical dimensions within a society. The cultural context plays a crucial role in shaping knowledge and identity, providing significance and direction to human life, and, as a result, affecting aspects related to mental health such as anxiety and depression. This implies that the context has an impact not only on how MPA is experienced but also on how it is perceived and addressed by higher music education institutions.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p40
|
PMC11276725
|
sec[3]/p[9]
|
Discussion
| 2.470703 |
biomedical
|
Study
|
[
0.5625,
0.0010728836059570312,
0.436279296875
] |
[
0.9765625,
0.01398468017578125,
0.0089111328125,
0.0003612041473388672
] |
Barros’ systematic review showed that both the contextual factor of the performance situation and the behavioral factor are predictors of MPA. However, in this study, the contextual dimension was associated with the physiological factor (CPF) and the behavioral dimension was associated with the emotional factor (BEF) for better adjustment indices, suggesting two new variables to consider in future research. Furthermore, these variables can also support decision-making to implement specific interventions involving music students.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p41
|
PMC11276725
|
sec[3]/p[10]
|
Discussion
| 2.695313 |
other
|
Study
|
[
0.21142578125,
0.0007982254028320312,
0.78759765625
] |
[
0.9951171875,
0.0037097930908203125,
0.0008726119995117188,
0.00013494491577148438
] |
This study has some limitations that can be addressed by future research. Since the PoMPAS ( Appendix 1 ) is a self-report questionnaire, its limitations are inherent to the type of instrument itself (it only assesses MPA globally). The sample in this study was convenience-based, which hinders generalizations. Furthermore, other questionnaires that could test convergent and divergent validity were not applied, which may be the main shortcoming of this study. Thus, we suggest that future studies include this validation with different scales, seeking to identify possible weaknesses. Despite this, the PoMPAS has proven to be a reliable tool with good psychometric qualities, developed and validated to measure MPA in the context of higher music education in Portugal.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p42
|
PMC11276725
|
sec[4]/p[0]
|
Data availability statement
| 0.942871 |
other
|
Other
|
[
0.037811279296875,
0.0015344619750976562,
0.96044921875
] |
[
0.0015716552734375,
0.99755859375,
0.00034880638122558594,
0.00034737586975097656
] |
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276725_p43
|
PMC11276725
|
sec[5]/p[0]
|
Ethics statement
| 1.115234 |
biomedical
|
Other
|
[
0.9296875,
0.00229644775390625,
0.0679931640625
] |
[
0.04266357421875,
0.95556640625,
0.0009059906005859375,
0.0009870529174804688
] |
The studies involving humans were approved by the Ethics and Deontology Board of the University of Aveiro . The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276725_p44
|
PMC11276725
|
sec[6]/p[0]
|
Author contributions
| 0.944336 |
other
|
Other
|
[
0.2203369140625,
0.004467010498046875,
0.775390625
] |
[
0.0030918121337890625,
0.99609375,
0.0002925395965576172,
0.0004208087921142578
] |
SB: Conceptualization, Investigation, Writing – original draft, Writing – review & editing, Methodology, Data curation. AF: Data curation, Formal analysis, Software, Validation, Writing – review & editing. HM: Methodology, Supervision, Writing – review & editing. AP: Supervision, Writing – review & editing.
|
[
"Samuel Barros",
"Alex França",
"Helena Marinho",
"Anabela Pereira"
] |
https://doi.org/10.3389/fpsyg.2024.1436216
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276737_p0
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PMC11276737
|
sec[0]/p[0]
|
1. Introduction
| 4.226563 |
biomedical
|
Review
|
[
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[
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Caffeic acid (CA) was first identified by Hlasiwetz in 1867 during the hydrolysis of caffetannic acid using caustic potash . CA is a naturally occurring polyphenol found widely in the plant kingdom, particularly in beverages like coffee and yerba mate, which are consumed worldwide. Polyphenols are characterized by a benzene structure functionalized with one or more hydroxyl groups. Presently, there are over 8000 known polyphenolic compounds, categorized into various families, Figure 1 , including phenolic acids (such as hydroxybenzoic acids and hydroxycinnamic acids), flavonoids (encompassing flavones, flavonols, flavonones, isoflavones, flavononols, anthocyanins, flavan-3-ols, and chalcones), tannins (both hydrolysable and non-hydrolysable (condensed) tannins), stilbenes, lignans, quinones (benzoquinone, naphthoquinone, and anthraquinones), and coumarins (simple coumarins, furanocoumarins, pyranocoumarins, benzocoumarins, coumestans, and biscoumarins) .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276737_p1
|
PMC11276737
|
sec[0]/p[1]
|
1. Introduction
| 4.882813 |
biomedical
|
Study
|
[
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[
0.97705078125,
0.0011348724365234375,
0.0213165283203125,
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The properties of CA stem from its distinctive chemical structure. The presence of phenolic hydroxyl groups in the catechol moiety, coupled with a double bond in the carbon chain, imparts both antioxidant and pro-oxidant characteristics to CA. Within cells, CA serves as a primary antioxidant by counteracting harmful reactive oxygen species (ROS) that pose threats to deoxyribonucleic acid (DNA), proteins, and lipids, thus mitigating the risk of carcinogenesis. Moreover, CA exhibits secondary antioxidant activity by stimulating the intracellular nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathway. The Nrf2 regulates the expression of phase II antioxidant enzymes, including glutathione S-transferase (GST), heme oxygenase 1 (HO-1), and NADPH Quinone Dehydrogenase 1 (NQO1), which play pivotal roles in preserving cellular redox homeostasis . Research has shown that CA exhibits hepatoprotective properties in HepG2 cells, shielding them from oxidative stress triggered by tert-butyl hydroperoxide (t-BHP). This suggests that the activation of Nrf2 and a rise in levels of HO-1 and glutamate-cysteine ligase (GCL) within the cell nuclei occur in response . Furthermore, CA has been shown to mitigate cell and tissue damage in the brains of rats exposed to neurotoxic compounds such as quinolinic acid (QUIN, 100 μM), ferrous sulfate (FeSO 4 , 25 μM), and 6-hydroxydopamine (6-OHDA, 100 μM). At a concentration of 100 μM, CA reduced oxidative damage and improved brain function in rats. Similar findings were observed in the worm model C. elegans , where CA directly activated the Nrf2/ARE pathway . Additionally, CA has been found to down-regulate inflammatory interleukins, specifically interleukin-6 (IL-6) and interleukin-1β (IL-1β), as well as nuclear factor kappa B (NF-κB) in the inflammatory cascade and inhibit signal transducer and activator of transcription 3 (STAT3) and signal-regulated kinase 1/2 (ERK1/2) actions in vitro . However, an antioxidant agent such as CA can become a pro-oxidant due to its ability to chelate metals such as copper (Cu), inducing lipid peroxidation and causing DNA damage through oxidation or the formation of covalent adducts with DNA .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p2
|
PMC11276737
|
sec[0]/p[2]
|
1. Introduction
| 4.078125 |
biomedical
|
Review
|
[
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[
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These actions play a vital role in both cancer prevention and treatment. Furthermore, evidence indicates that caffeic acid might enhance the susceptibility of cancer cells to certain drugs frequently employed in chemotherapy, implying its potential as a promising compound for combating chemoresistance. This review aims to underscore the phytochemical characteristics of CA and its direct involvement in cellular pathways linked to cancer development and advancement, in contrast to other reviews that demonstrate the general activity of CA. Here, we provide a strong basis for the use of CA as an adjuvant in cancer chemotherapy and radiotherapy.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p3
|
PMC11276737
|
sec[1]/p[0]
|
2. Methodology
| 3.90625 |
biomedical
|
Review
|
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[
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The literature review was conducted across multiple databases, including Google Scholar, PubMed, and Springer . Initially, a search was conducted using keywords such as caffeic acid, chemoresistance, adjuvant, biosynthesis, and metabolism. Subsequently, additional terms like inflammation and molecular targets were combined with caffeic acid for a more comprehensive search. The literature exploration involved examining the bibliographies of selected publications featuring original research to compile this review article.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p4
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PMC11276737
|
sec[2]/p[0]
|
3. Biosynthesis of Caffeic Acid
| 4.566406 |
biomedical
|
Study
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CA is synthesized via the phenylpropanoid pathway, which originates from the amino acids phenylalanine or tyrosine. Tyrosine undergoes a two-step conversion process to produce p -coumaric acid, initially catalyzed by the enzyme tyrosine ammonia-lyase (TAL). Subsequently, p -coumaric acid is transformed into CA by 4-coumarate 3-hydroxylase (C3H), which introduces a hydroxyl group at position 3. Another route involves the conversion of p -coumaric acid to coumaroyl-CoA by 4-coumarate (i.e., CoA ligase (4CL)), followed by m -hydroxylation by C3H to yield caffeoyl-CoA. The hydrolysis of caffeoyl-CoA by CoA thioesters results in the production of caffeic acid and CoA . The enzymes involved in this biosynthetic pathway have been elucidated through knockout mutations and RNAi-mediated studies in Arabidopsis plants, facilitating the identification and functional characterization of key genes and enzymes . Figure 3 shows a schematic representation of the biosynthetic pathway.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276737_p5
|
PMC11276737
|
sec[3]/p[0]
|
4. Natural Sources with High Content of CA
| 4.152344 |
biomedical
|
Review
|
[
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CA is abundantly present in a wide range of plant-derived foods, including fruits, vegetables, and certain beverages. The concentration of CA within a particular plant species varies depending on factors such as the plant part (e.g., fruits, leaves, stems, and roots), degree of ripeness, processing techniques, and storage conditions. Natural sources rich in CA include coffee beans, especially when freshly roasted, which can contain significant amounts of CA depending on the coffee type and brewing method . Fruits such as apples, pears, cherries, and grapes are known to contain CA , while vegetables like bell peppers, broccoli, carrots, and spinach also contribute to CA intake . Herbs and spices like thyme, oregano, sage, rosemary, and basil are recognized as rich sources of CA . Additionally, whole grains like wheat, oats, and rice, particularly their bran and outer layers, contain this polyphenol . Recent research has revealed the presence of CA in certain mushrooms, including Agaricus bisporus , Coprinus atramentarius , Morchella elata , and Laetiporus sulphureus . Furthermore, the traditional consumption of artichoke ( Cynara scolymus ) has been identified as a significant source of CA, particularly in its leaves . The Phenol-Explorer database ( http://phenol-explorer.eu/ ) offers comprehensive information on polyphenol levels in various foods, comprising over 35,000 data points encompassing 500 distinct polyphenols across more than 400 food items. Table 1 provides an overview of the major natural sources of CA.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276737_p6
|
PMC11276737
|
sec[4]/p[0]
|
5. Absorption, Distribution, and Metabolism of CA
| 4.136719 |
biomedical
|
Study
|
[
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The potential therapeutic use of CA relies heavily on its pharmacokinetic behavior, which encompasses its stability within the digestive system, including exposure to acidic pH, bile, and metabolic enzymes, as well as its absorption in the intestines, distribution throughout the body, and subsequent metabolic processes leading to excretion. Studies have demonstrated that CA can traverse the blood–brain barrier (BBB) and reach concentrations of 0.02 µM in the cerebrospinal fluid, thereby exerting beneficial effects on the brain . To investigate the pharmacokinetics of CA, experiments were conducted in rats using radioactive-labeled CA [3- 14 C]. Rats were orally administered 1.52 mg of labeled CA [3- 14 C] (140 × 10 6 dpm) via gavage, and various samples, including organs, tissues, plasma, urine, and feces, were collected over a duration of up to 72 h. These samples were then analyzed using high-performance liquid chromatography (HPLC) coupled with online radioactivity detection and tandem mass spectrometry, allowing for the determination of residual radioactivity in the samples. The results of these analyses are summarized in Table 2 .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276737_p7
|
PMC11276737
|
sec[4]/p[1]
|
5. Absorption, Distribution, and Metabolism of CA
| 4.199219 |
biomedical
|
Study
|
[
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[
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One hour after ingestion, approximately 80% of the radioactivity remained in the gastrointestinal (GI) tract, while the remaining 20% had already entered the bloodstream and kidneys. This indicates that the absorption of CA starts in the stomach and is subsequently excreted, primarily through urine, in the form of nine identified radioactive compounds, including trans -caffeic acid, cis -caffeic acid, caffeic acid 3′- O -sulfate, caffeic acid-4′- O -sulfate, caffeic acid 3′- O -glucuronide, caffeic acid 4′- O -glucuronide, isoferulic acid-3′- O -sulfate, ferulic acid-4′- O -sulfate, and ferulic acid-4′- O -glucuronide , along with four unidentified metabolites. By the 72-h mark, there was minimal to no accumulation of radioactivity in various body tissues, including the kidney, brain, testes, lung, heart, muscle, liver, spleen, and red blood cells. Only a small quantity of an unidentified 14 C-labeled metabolite was excreted in feces. The overall recovery of radioactivity was approximately 80% .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276737_p8
|
PMC11276737
|
sec[4]/p[2]
|
5. Absorption, Distribution, and Metabolism of CA
| 4.09375 |
biomedical
|
Study
|
[
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[
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Kishida and Matsumoto conducted a study on the metabolism of CA in male Wistar rats that were administered a dosage of 40 mg/kg. They found that at 48 h after administration, approximately 61.6% of CA was excreted, with the excretion primarily consisting of glucuronidated and/or sulfated CA-conjugates. To analyze these conjugates and quantify the amount of free CA, specific enzymes were utilized to release CA from the conjugates. Subsequently, CA levels in the urine were measured using HPLC-DAD .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p9
|
PMC11276737
|
sec[5]/p[0]
|
6. Signaling Pathways Affected in Cancer Progression
| 4.167969 |
biomedical
|
Review
|
[
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[
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Despite continuing advances in treatments, cancer remains a major health challenge, with cardiovascular diseases and cancers being the most common causes of death worldwide . Understanding the detailed mechanisms of carcinogenesis, which are triggered by prolonged exposure to various risk factors, is crucial for preventing cancer development and progression . Hanahan and Weinberg have summarized several cellular processes that contribute to the emergence of neoplasms and their malignant progression, including self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, unlimited replicative potential, tissue invasion and metastasis, and sustained angiogenesis .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276737_p10
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PMC11276737
|
sec[5]/p[1]
|
6. Signaling Pathways Affected in Cancer Progression
| 4.925781 |
biomedical
|
Study
|
[
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Although cancer is a multifactorial disease, a common outcome of exposure to risk factors is inflammation and uncontrolled production of ROS. ROS and RNS are a group of radical and non-radical molecules produced by cellular metabolism or induced by external sources. Excessive ROS formation can damage macromolecules such as DNA, proteins, and lipids, leading to genomic instability and altered cell growth . ROS can influence cell cycle progression by affecting the activity of proteins like cyclin-dependent kinase inhibitor p21 or the serine/threonine mutant ataxia telangiectasia protein kinase (ATM). ATM is crucial for DNA repair and impacts cell signaling pathways that are important for proliferation and apoptosis, such as the Akt or p53 pathway . Normally, intracellular ROS accumulation due to carcinogen exposure is mitigated by antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD), or the glutathione (GSH) system. However, when ROS levels exceed the cell’s antioxidant capacity, extensive oxidative damage to cellular components occurs, increasing the likelihood of mutations in oncogenes or tumor suppressor genes and leading to the formation of precancerous lesions. Consequently, ROS are attributed to a tumor-promoting role during carcinogenesis as they can inactivate or activate proteins involved in cancer-related signaling pathways.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276737_p11
|
PMC11276737
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sec[5]/p[2]
|
6. Signaling Pathways Affected in Cancer Progression
| 4.996094 |
biomedical
|
Review
|
[
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ROS, chronic infections, and inflammation all activate the NF-κB pathway, promoting the dimerization of the inhibitor of κB kinase (IKK) gamma (IKKγ), also known as the nuclear factor κB (NF-κB) essential modulator (NEMO). This component of the IKK complex is crucial for the canonical activation of the NF-κB pathway . The dimerization of IKKγ/NEMO triggers the phosphorylation of inhibitory NF-κB proteins (IκBs), leading to their degradation by the proteasome. This process induces the phosphorylation of p50/p65 dimers via the activation of protein kinase-A (PKAc), facilitating the translocation of NF-κB to the nucleus, where it regulates the transcription of genes associated with survival, cell proliferation, proinflammatory cytokines, and ROS-related genes . The activation of the NF-κB signaling pathway is linked to various cellular processes, including inflammation and immune response. The disruption of this pathway has been associated with inflammatory diseases and the development and progression of cancer. In cancer, specifically, NF-κB activation is linked to apoptosis resistance as it negatively regulates anti-apoptotic proteins B-cell leukemia/lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-XL). It is also linked to increased malignancy by modulating the transcription of genes related to cell proliferation of cyclin D1 (CCND1) and cellular Myc (c-Myc). It also influences the expression of genes involved in angiogenesis, such as vascular endothelial growth factor (VEGF), proinflammatory cytokines related to carcinogenesis, such as IL-1β and IL-6, genes involved in detoxification and drug resistance, and antioxidant enzymes such as SOD, CAT, thioredoxin (TRX), HO-1, and glutathione peroxidase (GPX1) .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p12
|
PMC11276737
|
sec[5]/p[3]
|
6. Signaling Pathways Affected in Cancer Progression
| 4.996094 |
biomedical
|
Study
|
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Another pathway activated by ROS is the Nrf2 pathway. Nrf2 is a key regulator of cellular redox homeostasis, controlling the expression of various antioxidant and cytoprotective genes involved in drug detoxification, cell proliferation, metabolism, autophagy, apoptosis, proteasome function, DNA repair, and antioxidant response, collectively known as phase II genes. Under normal conditions, Nrf2 associates with the Kelch-like Echassociated protein 1 (Keap1), part of the Cullin 3 (CUL3)-based ubiquitin ligase complex that regulates Nrf2 stability, and promotes its degradation via the ubiquitin/proteasome pathway. However, in the presence of electrophilic molecules or oxidative stress, cysteine residues in Keap1 are modified, leading to its inactivation and reducing its binding to Nrf2 or CUL3, thereby preventing Nrf2 degradation. Stabilized Nrf2 translocates to the nucleus, where it dimerizes with other leucine zipper proteins of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (Maf) family to activate AREs on phase II genes. Additionally, Nrf2 degradation can be mediated by β-transducin repeat-containing protein (β-TrCP) in the nucleus, which binds to phosphorylated Nrf2 and Cullin 1 (CUL1), inducing Nrf2 ubiquitination. Another mechanism involves Keap1 degradation mediated by phosphorylated p62/Sequestosome-1 (p62/SQSTM1) . Strong cellular antioxidant, drug-detoxifying, and cytoprotective activities have been linked to cancer malignancy, with evidence showing that cancer cells often exhibit aberrant Nrf2 activation. Various mechanisms have been identified, including somatic mutations in Nrf2, Keap1, or CUL3 genes, epigenetic silencing of Keap1, accumulation of Keap1-interacting proteins like p62/SQSTM1 or p21, and cysteine modification by oncometabolites such as fumarate, which affect Keap1 activity . Nrf2 activation has been associated with resistance to chemotherapy and radiotherapy and poor prognosis in cancers such as head and neck, lung, ovarian, and breast cancer . Importantly, several natural and chemical compounds are being tested to inhibit Nrf2 signaling in cancer cells with high Nrf2 activity, while Nrf2 inducers are being explored to protect normal cells from carcinogens .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276737_p13
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6. Signaling Pathways Affected in Cancer Progression
| 4.878906 |
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Study
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Oxygen deprivation in tumors significantly influences cancer development and metastasis. Hypoxia-inducible transcription factors (HIFs) are crucial in promoting the survival, proliferation, adaptability, and motility of malignant cells. Additionally, hypoxia elevates Programmed death-ligand 1 (PD-L1) expression, also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1), in both malignant and immunoregulatory cells . ROS also play a role by oxidizing prolyl hydroxylase domain (PHDs) proteins, essential for the binding of von Hippel–Lindau tumor suppressor protein (p-VHL) to HIF-1α, leading to its ubiquitination and degradation in the proteasome. HIF-1 operates as a heterodimeric complex composed of an alpha and a beta subunit. HIF-1β is constitutively expressed, while HIF-1α accumulation is induced under hypoxic conditions. In normoxia, PHDs hydroxylate two prolyl residues of HIF-1α, marking it for ubiquitination and subsequent von Hippel–Lindau (VHL) complex-mediated degradation . Conversely, during hypoxia, HIF-1α accumulates, and the HIF-1 complex activates the transcription of genes containing hypoxia response elements (HREs) in the cell nucleus. HIF-1 signaling has been extensively studied in various cancers, including pancreatic, gastric, and prostate cancers, due to its regulation of genes involved in angiogenesis, metabolism, glucose transport, and cell migration .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p14
|
PMC11276737
|
sec[5]/p[5]
|
6. Signaling Pathways Affected in Cancer Progression
| 4.707031 |
biomedical
|
Review
|
[
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[
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In neoplastic cells, the ErbB family of proteins and their signaling pathways are frequently altered. This family consists of four receptor tyrosine kinases related to the epidermal growth factor receptor (EGFR); the name of the family is derived from the viral oncogene homologous to erythroblastic leukemia viral oncogene. In humans, this family includes Human epidermal growth factor receptor 1 or Her 1 (EGFR, ErbB1), Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4) . ErbB signaling influences cell proliferation, migration, differentiation, apoptosis, and motility via the Phosphoinositide 3-kinase/serine threonine-protein kinases (PI3K/Akt), the Janus kinase/signal transducer and activator of transcription (JAK/STAT), and Mitogen-activated protein kinase (MAPK) pathways. Aberrant signaling of ErbB family members is critical in tumorigenesis and immune evasion in various malignancies. Excessive ErbB signaling is linked to the development of numerous solid tumors, and direct alterations in these receptor-dependent pathways are associated with cancer progression .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p15
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PMC11276737
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sec[5]/p[6]
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6. Signaling Pathways Affected in Cancer Progression
| 4.988281 |
biomedical
|
Review
|
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The PI3K/AKT pathway is pivotal for cell survival, proliferation, and protein biosynthesis. Phosphoinositide 3-kinase (PI3K) is a family of lipid kinase enzymes that phosphorylate the 3’-OH group of phosphatidylinositols (PtdIns) in the plasma membrane (Class I) or intracellular membranes for vesicular trafficking regulation (Classes II and III). These proteins are biologically significant as their activation influences cellular processes such as growth, survival, metabolism, inflammation, motility, proliferation, and therapy resistance . Class I PI3K and its downstream effector AKT/PKB are activated by extracellular growth factors like epidermal growth factor (EGF), platelet-derived growth factor (PDGF), or insulin, triggering a phosphorylation cascade that culminates in the activation of the mammalian target of rapamycin (mTOR) kinase and the Ras/MAPK pathway. Ras proteins, from the acronym Rat sarcoma virus, are located in the plasma membrane of cells and act as molecular switches that send signals to activate cell growth. The Ras family is a protein superfamily of small GTPases. Members of the superfamily are divided into families and subfamilies based on their structure, sequence, and function. The five main families are Ras, Ras homologous (Rho), Ras-related nuclear protein (Ran), Ras-related in brain (Rab), and ADP-ribosylation factor (Arf) GTPases. The activation of the PI3K/AKT pathway is widely associated with carcinogenesis and is frequently observed in various human cancers . High levels of ROS can oxidize and inactivate the phosphatase and tensin homolog (PTEN), promoting PI3K/AKT pathway activation . PTEN acts as a phosphatase to dephosphorylate PtdIns, counteracting PI3Ks by specifically catalyzing the dephosphorylation of the 3phosphate of the inositol ring at phosphatidylinositol 3,4,5-trisphosphate (PIP3) to produce phosphatidylinositol 3,4-bisphosphate (PIP2). This dephosphorylation is crucial because it inhibits the Akt signaling pathway; thus, sustained PTEN inactivation leads to excessive PI3K/AKT pathway activation . The PTEN phosphatase is encoded by the PTEN tumor suppressor gene, and mutations or deletions of this gene contribute to constitutive PI3K/AKT signaling, facilitating the development of cancers such as glioblastoma, lung cancer, breast cancer, and prostate cancer . Clinical trials are currently investigating PI3K/AKT pathway inhibition for treating pancreatic, lung, ovarian, breast, melanoma, and hematological malignancies .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11276737_p16
|
PMC11276737
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6. Signaling Pathways Affected in Cancer Progression
| 5.042969 |
biomedical
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Study
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Mitogen-activated protein kinases (MAPKs) are a group of enzymes that phosphorylate various cellular proteins, including transcription factors, nuclear proteins, membrane transporters, cytoskeletal elements, and other kinases, upon activation. This phosphorylation regulates crucial cellular processes, such as proliferation, migration, differentiation, senescence, and cell death. MAPKs are activated by extracellular signals like growth factors (EGF, PDGF, insulin), cytokines, and intracellular stressors. Key MAPK subfamilies, such as ERK1/2, Jun N-terminal kinase (JNK), and p38, respond to different stimuli. The Ras/Raf/MEK/ERK1/2 pathway is notably relevant in cancer, often altered by excessive growth factors, hormonal signaling, or oncogenic mutations, leading to abnormal mitogenic signaling, increased proliferation, and apoptosis resistance. Raf is an acronym for Rapidly Accelerated Fibrosarcoma and is the best characterized Ras effector and a member of a family of serine/threonine kinases. Mutations in Ras family genes, found in about 30% of human cancers, activate proteins like PI3K, Rac, and Rho, which influence cytoskeletal dynamics and cell invasiveness. Rac-GTPase represents a subfamily of the Rho family. Specific small molecule inhibitors targeting the Ras/MAPK pathway are under clinical trials, including those for the KRAS-G12C mutation, with promising clinical outcomes anticipated. The Ras/MAPK pathway activation is intricately regulated and closely linked to ROS production. ROS can directly activate MAPKs without external stimuli like EGF, and antioxidant inhibition has been shown to prevent this activation in various experimental setups. Ras-mediated transformation involves NADPH oxidase 1 (NOX1) activation via the Ras-Rac1-NOX1 pathway. Key redox sensors in the MAPK cascade include TRX and apoptosis signal-regulating kinase 1 (ASK1). TRX inhibits ASK1 when reduced, but ROS-induced oxidation releases ASK1, activating JNK and p38 signaling, which affects cell proliferation, differentiation, apoptosis, inflammation, and stress response. Additionally, ROS can activate ERK signaling, potentially through the upstream activation of the EGF receptor (EGFR). This process involves NOX-mediated H2O2 generation and SHP-2 phosphatase inactivation, sustaining EGFR activation and promoting cell signaling via the Ras-Raf-MEK-ERK pathway, impacting cell proliferation and differentiation. MAPK activation is also linked to mitochondrial changes, including increased mitochondrial ROS production. Mutations in Ras or ERK2 activation can induce mitochondrial fission and increase mitochondrial mass, affecting ATP production and contributing to cancerous traits in cells with Ras mutations .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p17
|
PMC11276737
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sec[5]/p[8]
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6. Signaling Pathways Affected in Cancer Progression
| 4.980469 |
biomedical
|
Review
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The intracellular JAK/STAT pathway and modification of histone marks on nucleosomes regulate the expression of proinflammatory mediators, playing a crucial role in carcinogenesis . The activation of the JAK/STAT pathway occurs in response to various hormones (prolactin, growth hormone, leptin, and erythropoietin), cytokines, and growth factors through their respective receptors. This signaling pathway regulates cell proliferation, differentiation, survival, motility, and apoptosis in different tissues . STATs are latent cytoplasmic transcription factors activated by phosphorylation through Janus kinase (JAK). The JAK family includes JAK1-3 and tyrosine kinase 2 (TYK2), which interact non-covalently with membrane receptor domains or intracellular portions of growth factor receptors. Upon cytokine binding, JAKs phosphorylate tyrosine residues to transmit signals from membrane-bound receptors. Phosphorylated STAT molecules then dimerize and translocate to the nucleus, initiating gene transcription that regulates cell cycle progression, apoptosis initiation, and occurrence. These processes are vital for cellular homeostasis, and disruptions in this pathway contribute to cancer progression, inflammatory diseases, and autoimmune disorders. STAT family proteins are implicated in creating and sustaining a procarcinogenic inflammatory microenvironment, initiating malignant transformation, and promoting cancer progression. Inflammation plays a critical role in tumor initiation and progression, both as an initiator of oncogenic transformations and as a promoter through genetic and epigenetic alterations that foster an inflammatory microenvironment conducive to tumor growth. Additionally, immune responses and inflammatory mediators mediated by STAT3, STAT5, and STAT6 suppress antitumor immunity, further contributing to carcinogenesis. Given the JAK-STAT pathway’s role in regulating cell cycle and apoptosis effector molecules, it is evident that this pathway promotes carcinogenesis by enhancing proliferation and modulating programmed cell death .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p18
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PMC11276737
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6. Signaling Pathways Affected in Cancer Progression
| 5.042969 |
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In human cancer, the TP53 tumor suppressor gene, situated on chromosome 17, is the most frequently mutated. It encodes p53, a transcription factor binding to specific DNA sequences within the genome, activating adjacent genes and those controlled by enhancers with p53 binding sites. Additionally, p53 can repress the transcription of numerous genes, typically through indirect mechanisms . The primary biological role of p53 is well-understood: it induces cell cycle arrest, senescence, or apoptosis in response to DNA damage, thereby preventing the accumulation of oncogenic mutations, earning it the nickname “guardian of the genome”. Moreover, p53 participates in other cellular processes like autophagy, metabolism, and cellular plasticity . It enhances glutamine catabolism, supports antioxidant activity, reduces lipid synthesis, promotes fatty acid oxidation, and stimulates gluconeogenesis. Under normal conditions in unstressed cells, p53 levels remain low due to continuous proteasomal degradation mediated by the Mouse double minute 2 homolog (MDM2), an E3 ubiquitin ligase, and the principal inhibitor of p53, along with COP1 and p53-induced RING-H2 protein (Pirh2). Additionally, transformed mouse 3T3 cell double minute 4 (MDM4), formally named MDMX, restricts p53’s biochemical activity as a transcription factor, serving as a physiological inhibitor . At basal levels, p53 maintains the transcription of several antioxidant genes (SESN1/2, GPX1, and AIF). However, during stress conditions, p53 accumulates in the cytoplasm and induces the expression of NQO1 and proline oxidase (POX), enzymes that generate ROS, alongside Bcl2-associated X, apoptosis regulator (Bax), and p53-upregulated modulator of apoptosis (PUMA), which promote mitochondrial uncoupling and ROS production, culminating in oxidative stress and apoptosis. Bax and Bcl-2 homologous antagonist/killer (Bak) are members of the Bcl-2 family and core regulators of the intrinsic pathway of apoptosis. Upon apoptotic stimuli, they are activated and oligomerized at the mitochondrial outer membrane (MOM) to mediate its permeabilization, which is considered a key step in apoptosis. PUMA is a proapoptotic homolog domain-3-only member of the Bcl-2 protein family, which has been demonstrated to be critical for some cells’ apoptosis induced by ER stress. A crucial target of p53 involved in ROS metabolism and regulation is the TP-53-induced regulator of apoptosis and glycolysis (TIGAR), which inhibits glycolysis and enhances glucose flux into the pentose phosphate pathway, a major source of NADPH utilized in reducing GSH. Conversely, p53 mutations in cancer cells impair mitochondrial respiration and elevate glycolysis .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p19
|
PMC11276737
|
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6. Signaling Pathways Affected in Cancer Progression
| 3.330078 |
biomedical
|
Other
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In summary, multiple pathways and factors contribute to the emergence and progression of various cancers. Investigating the dysregulation of intracellular pathways in cancer and exploring molecules capable of restoring these pathways are crucial endeavors.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276737_p20
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PMC11276737
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7. Anti-Inflammatory Activity of Caffeic Acid against Cancer
| 4.21875 |
biomedical
|
Review
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[
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As mentioned in the previous section, chronic inflammation has been linked to the initiation and progression of cancer . ROS and RNS, generated during inflammation, can inflict DNA damage, potentially leading to mutations that contribute to the maintenance of tumors . Chronic inflammation often triggers cellular proliferation as part of tissue repair mechanisms, inadvertently creating conditions favorable for the expansion of cells with damaged DNA or mutations, thus heightening cancer risk. Moreover, inflammation has been implicated in cancer progression by promoting the production of inflammatory cytokines that support cell proliferation, inhibit apoptosis, stimulate tumor angiogenesis and vascularization, and facilitate tumor invasion and metastasis.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p21
|
PMC11276737
|
sec[6]/p[1]
|
7. Anti-Inflammatory Activity of Caffeic Acid against Cancer
| 4.300781 |
biomedical
|
Study
|
[
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NF-κB is a crucial protein complex responsible for controlling DNA transcription, cytokine synthesis, and cell viability. The dysregulation of NF-κB is associated with immune response irregularities and cancer advancement, making it a significant factor in tumor biology. It influences pathways like JNK/p38 MAPK and positively regulates c-Myc, thus playing a role in various reported neoplasms. Consequently, the inhibition of NF-κB holds promise as a target for cancer therapy development . In this context, CA has shown the capability to regulate this pathway, thereby disrupting cancer cell proliferation, viability, and invasion in endothelial cells, triggered by lipopolysaccharide (LPS), as well as in mammary epithelial cells . Consequently, CA modulation of cytokines may affect the production and function of various inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukins IL-1β, IL-6, and IL-8 .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p22
|
PMC11276737
|
sec[6]/p[2]
|
7. Anti-Inflammatory Activity of Caffeic Acid against Cancer
| 4.277344 |
biomedical
|
Study
|
[
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CA has been discovered to impede Cyclooxygenase-2 (COX-2), an enzyme pivotal in the inflammatory cascade. Elevated COX-2 expression is evident during prolonged inflammation, where it can foster the onset and progression of chronic ailments, such as cancer. Studies suggest that CA, at concentrations ranging from 50 to 10 µM, effectively suppresses COX-2 and its byproduct, prostaglandin E2 (PGE2), in human colon myofibroblast cells (CCD-18Co) . Consequently, CA also hampers the enzyme Nitric Oxide Synthase (iNOS), curtailing nitric oxide (NO) production, which may aid in inhibiting tumor angiogenesis .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p23
|
PMC11276737
|
sec[6]/p[3]
|
7. Anti-Inflammatory Activity of Caffeic Acid against Cancer
| 4.472656 |
biomedical
|
Study
|
[
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Inflammation induces the secretion of molecules like VEGF, which stimulates the development of new blood vessels that are crucial for supplying oxygen and nutrients to tumors. The activity of VEGF is amplified by HIF-1α and STAT3. In a Caki-I carcinoma animal model, CA was observed to suppress STAT3 phosphorylation, thus diminishing its function and consequently impeding HIF-1α, resulting in reduced tumor vascularization and VEGF gene expression . In retinal endothelial cells, CA demonstrated potent anti-angiogenic effects, mitigating vaso-proliferative retinopathies associated with ROS-induced VEGF . In hepatocellular carcinoma cells (HCC), CA curbed VEGF and vascularization induced by CoCl 2 , accomplishing this through the stabilization of STAT3/JNK1/HIF-1α . Guo et al. discovered that CA serves as a potent inhibitor of prolyl hydroxylase-2 (PHD2), an enzyme responsible for HIF hydroxylation and degradation. In neuronal cells such as PC12 and SH-SY5Y, CA attenuated cell apoptosis induced by hypoxia. Furthermore, in mice, CA administration decreased injury markers such as lactate dehydrogenase, malondialdehyde, and lactic acid .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11276737_p24
|
PMC11276737
|
sec[6]/p[4]
|
7. Anti-Inflammatory Activity of Caffeic Acid against Cancer
| 4.261719 |
biomedical
|
Study
|
[
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[
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Another process associated with inflammation in cancer is the production of enzymes such as metalloproteinases (MMPs), which play a role in breaking down the extracellular matrix of cells. MMP-2 and MMP-9 can degrade these barriers, facilitating the invasion of cancer cells into nearby tissues and their spread to distant areas. Through computational studies, CA has been identified as an inhibitor of MMP-9 and dipeptidyl peptidase-4 (DPP-4) enzymes, with respective IC 50 values of 158.19 and 88.99 µM . Chung et al. explored the enzymatic inhibitory effects of CA extracted from Euonymus alatus and its synthetic derivative caffeic acid phenethyl ester (CAPE) in animal experiments using rats. The animals were administered CA and CAPE at doses of 5 mg/kg subcutaneously or 20 mg/kg orally. Both compounds exhibited the inhibition of MMP-2 and -9, with no effect on MMP-1, -3, and -7. Moreover, in xenograft models, CA and CAPE hindered the growth of HepG2 tumors and liver metastasis by suppressing MMP-9 activity and decreasing NF-κB expression . These multifaceted mechanisms orchestrated by CA in cancer progression are depicted in Figure 5 .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p25
|
PMC11276737
|
sec[7]/p[0]
|
8. Caffeic Acid Properties against Cancer
| 4.554688 |
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|
Study
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Apoptosis, a regulated cell death mechanism, serves to eliminate damaged or unnecessary cells. CA has demonstrated the ability to trigger apoptosis in cancer cells by influencing the mitochondrial pathway. This is accomplished by the inhibition of the Bcl-2 family of proteins, leading to an increase in pro-apoptotic members (such as Bax and Bak) and a decrease in anti-apoptotic ones (such as Bcl-2 and Bcl-xL) . This action can result in the release of cytochrome c from the mitochondria into the cytosol, initiating the activation of caspases—protease enzymes crucial for programmed cell death . Specifically, CA at a concentration of 10 µg/mL can activate both initiator caspases (like caspase-9) and executioner caspases (such as caspase-3 and caspase-7), leading to the breakdown of cellular components necessary for apoptosis . Furthermore, CA has been found to induce the expression of p53, a tumor suppressor protein pivotal in preventing cancer development . The activation of p53 can result in cell cycle arrest and apoptosis.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276737_p26
|
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|
sec[7]/p[1]
|
8. Caffeic Acid Properties against Cancer
| 4.363281 |
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In general, it has been shown that CA is a potent modulator of apoptosis and autophagy in cancer cells, thus affecting their proliferation and survival, including in carcinoma cells in the head and neck and MCF-7 , multiple myeloma , leukemia (K562) , and osteosarcoma cells (MG-63) . In human melanoma SK-Mel-28 cells, the administration of CA (0–200 μM) induces apoptosis and cell cycle arrest by increasing the expression profile of caspase 1 and caspase 3 . Moreover, CA (200–800 μM) has been shown to promote Ca 2+ accumulation in cells in a concentration-dependent manner, an effect that is closely related to apoptosis. CA releases Ca 2+ from the endoplasmic reticulum by inducing protein phospholipase C and then induces apoptosis in SCM1 gastric cancer cells . In vivo, the effect of novel caffeic acids conjugated with silver nanoparticles with and without gamma radiation exposure has been found to be effective against experimentally induced Ehrlich tumors, resulting in growth inhibition in solid tumor cells, whose underlying mechanism involves an apoptotic effect .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p27
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8. Caffeic Acid Properties against Cancer
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The impact of CA on mitochondria has been explored, particularly in breast cancer cells like MCF-7 and MDA-MB-468 cell lines. Treatment with CA at a concentration of 20 μM disrupts mitochondrial function, which leads to several effects: increased Caspase-9 activity, elevated levels of ROS, and a decrease in membrane potential (Δψm) . Additionally, it has been suggested that CA may specifically influence protein kinase C delta (PKCδ), a protein that is involved in apoptosis and affects mitochondria by reducing ΔΨm. Consequently, CA promotes apoptosis in MG-63 osteosarcoma cells by inducing the translocation of PKCδ to mitochondria and reducing ΔΨm, resulting in mitochondrial membrane potential (MMP) alterations . Additionally, an antioxidant derived from CA, known as AntiOxCIN6, has been developed. This compound is formed by linking the antioxidant core to the lipophilic TPP+ via a 10-carbon aliphatic chain. Interestingly, AntiOxCIN6 has demonstrated the potential to indirectly induce apoptosis. Despite increasing the antioxidant defense system, this complex is inefficient in eliminating ROS. Consequently, it affects mitochondrial function by impairing its ATP production capacity. Although this impairment does not directly affect cell viability, it sensitizes A549 adenocarcinoma cells to apoptotic death induced by cisplatin . A summary of both the anti-inflammatory and proapoptotic anticancer activity of CA can be seen in the flowchart in Figure 6 . Here, it is observed that CA affects signaling pathways that result in cell death, decreased proliferation, and migration of cancer cells, as well as a decrease in angiogenesis processes.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
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https://creativecommons.org/licenses/by/4.0/
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en
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8. Caffeic Acid Properties against Cancer
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Regarding the modulation of CA in oncogenic signaling pathways in cancer, it has been reported that the administration of CA (100 μM) alone or in combination with metformin (10 mM) is efficient in stimulating the AMPK signaling pathway, which acts by preventing de novo synthesis of unsaturated fatty acids, consequently reducing cancer cell survival . AMP-activated protein kinase (AMPK) is a vital enzyme in regulating cellular metabolism and maintaining energy balance. It also plays a significant role in tumor progression by influencing the expression of genes associated with invasion, metastasis, and angiogenesis. Consequently, activators of AMPK hold promise for exerting antitumor effects by augmenting sensitivity to chemotherapy and radiotherapy while mitigating metastasis . CA has also been found to disrupt the PI3K/Akt signaling pathway, both in laboratory studies and in living organisms. This interference shows promise in inhibiting the proliferation and self-renewal ability of cancer stem cells (CSCs). Such effects have been investigated in CSC populations derived from the human colon adenocarcinoma cell line HCT116 . In melanoma, TGFβ is one of the key signaling pathways in progression because, in some circumstances, it can provide the ideal microenvironment for tumor development. In this sense, a study showed that CA (1 mmol/L), together with a moderately potent SMF (0.7 T), decreased the expression of TGFβ, which could support anticancer therapy . Conversely, tissue transglutaminase type 2 (TG2) is an enzyme involved in apoptosis, wherein its activity, among other roles, stimulates caspase activation, a process often induced by oxidative stress. In this context, a study conducted by Feriotto et al. revealed that CA effectively stimulates the activation pathways of TG2. This was shown by the antiproliferative impact observed in the K562 cell line (chronic myeloid leukemia), which correlated with TG2 activity. Such activation of TG2 contributed to the elevation of ROS levels, consequently leading to cell death .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276737_p29
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sec[7]/p[4]
|
8. Caffeic Acid Properties against Cancer
| 4.460938 |
biomedical
|
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In hepatocellular carcinoma (HCC), CA inhibits the activity of GRP75 (75 KDa Glucose-Regulated Protein) induced by low doses of the carcinogen Benzo(a)pyrene (B[a]P) through both transcriptional and post-transcriptional modifications. This inhibition is closely linked to CA’s role as an inhibitor of NF-κB, which serves as an upstream transcriptional regulator of GRP75. Additionally, CA induces the cleavage of the GRP75–p53 complex, leading to the nuclear translocation and activation of p53. This promotes the induction or maintenance of anti-apoptotic capacity and multidrug resistance (MDR) characteristics in HCC. Given its pivotal role, GRP75 is implicated in the onset and progression of cancer .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
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|
9. Caffeic Acid as an Adjuvant for Chemotherapy
| 4.238281 |
biomedical
|
Review
|
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Drug resistance represents a significant obstacle to the success of chemotherapy in treating many types of human tumors, and the extent of its effect varies depending on factors such as the cancer type, the specific drug used, and patient-related factors . One mechanism through which cancer cells develop resistance to chemotherapy involves the overexpression of drug efflux pumps, such as P-glycoprotein (P-gp), which diminishes the intracellular concentration of chemotherapeutic drugs. CA has demonstrated the ability to regulate the activity of these pumps, potentially mitigating drug efflux and enhancing the retention of chemotherapeutic agents within cells, thus improving the effectiveness of cancer treatments. Research conducted by Teng et al. investigated the impact of CA on P-gp both in vitro and in silico. Their findings revealed that the combination of CA with chemotherapeutic agents like doxorubicin reduced the activity of P-gp, as indicated by lower IC 50 values in resistant cancer cells. Additionally, CA inhibited the efflux of rhodamine 123. In silico analysis suggested that CA binds to P-gp through polar interactions with specific residues, including Glu74 and Tyr117 . A search and compilation of studies where CA was tested as a coadjuvant for the treatment of various types of cancer are presented below, divided into in vitro trials, in vivo trials, and clinical trials.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
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9.1. In Vitro and In Vivo Trials
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CA exhibits adjuvant effects, enhancing the apoptotic response when combined with cisplatin in various cancer cell lines such as Lacks’ cervical cancer cells (HeLa), cervical cancer (CaSki), non-small cell lung cancer cell (A549), and hepatoblastoma cell line (HEPG2) . Additionally, Sirota et al. demonstrated that the combined treatment with cisplatin (5 µM) and CA (10 µM) restored the chemo-sensitizing effect against cisplatin-resistant ovarian endometrioid adenocarcinoma cells . This combined treatment resulted in a reduction of cell viability comparable to that achieved in sensitive cells treated solely with cisplatin at the same concentration. However, it was noted that pre-incubation with CA before cisplatin treatment could induce resistance by activating Nrf2. This highlights the importance of cautious examination when using CA as an adjuvant to cisplatin . On another note, the cocrystallization of CA with 5-fluorouracil (5-FU) has been found to enhance the physicochemical properties of 5-FU, such as solubility and tissue permeability. This synergistic interaction leads to an improved anticancer activity of 5-FU, as indicated by a combination index (CI) of less than 1 . Table 3 summarizes the results of in vitro and in vivo co-treatments using CA against cancer cells.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276737_p32
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9.1. In Vitro and In Vivo Trials
| 4.117188 |
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In a recent study examining the impact of caffeic acid on lung cancer cells, it was observed that CA effectively inhibits proliferation, migration, and apoptosis by targeting the TMEM16A protein, which is a calcium-activated chloride channel. The inhibitory concentration (IC 50 ) of CA for TMEM16A was determined to be 29.47 ± 3.19 μM. Further animal studies corroborated these findings, demonstrating a significant reduction in tumor size. Notably, when combined with 5.4 mg/kg caffeic acid and hydroxydaunorubicin (DOX) at a dosage of 4.1 mg/kg, the treatment resulted in an 85.6% reduction in tumor size and minimized adverse effects. In conclusion, the combined therapy of caffeic acid and DOX proved more effective in inhibiting lung cancer cell growth compared to either drug administered alone, even at higher doses .
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276737_p33
|
PMC11276737
|
sec[8]/sec[0]/p[2]
|
9.1. In Vitro and In Vivo Trials
| 4.398438 |
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|
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|
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In addition to the re-sensitization of cancer cells, a protective effect of CA towards other organs has also been seen during the use of chemotherapeutics. For example, the effect of CA encapsulated in a nanoemulsion on the reduction of nephrotoxicity towards non-cancerous cells of the HEK 293 renal line was evaluated, showing an improvement in cell viability in renal cells from 33% to more than 95% during treatment with cisplatin . This finding and similar results are also summarized in Table 3 . ijms-25-07631-t003_Table 3 Table 3 Synergetic effect of CA in cancer cells. Aim Cancer Type: Model Treatment Conditions Finding Reference To assess the efficacy of cisplatin + CA treatment in human cervical cancer • In vitro: human cervical cancer cell lines: HeLa, SiHa, CaSki (HPV-positive), and C33A (HPV- negative) cells. CA (300 µM) and cisplatin (11 µM) for 24 h The combination of cisplatin and CA significantly inhibited cell growth of HeLa and CaSki cell lines, with a combination index < 1, indicating a synergistic effect. The combination significantly increased the expression of caspases 3, 7, and 9, demonstrating apoptosis. To assess the efficacy of the combined treatment with cisplatin + CA against ovarian carcinoma • In vitro: ovarian carcinoma cells A2780 and ovarian carcinoma- resistant A2780cisR cells. CA (10 µM) and cisplatin (5 µM) for 24 h The combined therapy restores the sensitivity of resistant cells to cisplatin, achieving a similar level of cell viability as that observed in sensitive cells (60% viability). When the cisplatin/caffeic acid ratio was increased to 1:10 (5:50 µM), the caspase activity rose significantly by 4.3-fold. To evaluate the effects of metformin (Met) and CA on metastatic human cervical cancer • In vitro: metastatic human cervical HTB-34 cell line. CA (100 µM) and Met (10 mM) for 24 h CA (100 µM) and Met (10 mM) activated AMPK. CA increased oxidative stress, affecting bioenergetics pathways and making HTB-34 cells more sensitive to Met. CA and Met suppressed HTB-34 cells by different mechanisms. To determine the efficacy and underlying mechanisms of CA in combination with paclitaxel for the treatment in human non-small cell lung carcinoma (NSCLC) • In vitro: human non-small cell lung carcinoma H1299 cells. • In vivo: mouse xenograft model by subcutaneous injections of H1299 cells. In vitro: 100 μM CA + 10 μM of paclitaxel for 24 h In vivo: 20 mg/kg CA and 10 mg/kg paclitaxelad ministered concomitantly for three weeks. In vitro, combination treatment decreased the proliferation of NSCLC H1299 cells by the MAPK pathway. CA induced sub-G1 cell cycle arrest in H1299 cells. In vivo, the combined treatment with CA and paclitaxel exerted a more effective suppressive effect on tumor growth in H1299 xenografts without causing significant adverse effects. To evaluate the synergistic antitumor activity and the physicochemical and pharmacokinetic properties of caffeic acid/5-FU-cocrystal in vitro and in vivo. • In vitro: human colon cancer HCT-116, breast cancer MDA-MB-231, and lung cancer A549 cell lines • In vivo: Sprague Dawley rats In vitro: HCT-116; MDA-MB-231 (15.19 μM); and A549 (11.57 μM) of caffeic acid/5-FU cocrystal for 48 h. In vivo: oral dose of 50 mg kg −1 . In vitro: Cocrystallization of CA + 5-FU optimized the physicochemical properties of 5-FU and exerted a synergistic antitumor effect (CI < 1), thus enhancing the anticancer activity of 5-FU. In vivo: The aqueous solubility and permeability of 5-FU in the cocrystal increased by 1.92 and 4.22-fold, respectively, compared to the original drug 5-FU. To evaluate the effects of CA and imatinib (IM) and their synergistic effects on chronic myeloid leukemia model • In vitro: human myelogenous leukemia cell line K562 and (IM)-resistant cells. Synergistic effects of CA (up to 38 µM) and IM (up to 0.15 µM) on K562 cells. CA induced apoptosis in IM-resistant cells and reduced their proliferation. Combination treatment with CA and IM showed synergistic effects, increasing the antiproliferative activity. To assess the activity of Pancreatic Ductal Adenocarcinoma (PDAC) by treatment with CA, gemcitabine (Gem), and doxorubicin (DOX) • In vitro: Human epithelioid carcinoma attached cell lines Panc-1 and Mia-PaCa-2. Both have increased potential of migration and invasion, as well as Gem resistance Cytotoxic analysis of CA was measured at 24 and 48 h in combination with Gem and DOX. CA showed cytotoxic concentrations (IC 50 ) of 37.37 µM and 15.06 µM against Panc-1 and Mia-PaCa-2, respectively. Cotreatment with a combination of CA and Gem or DOX did not show synergic activity; in contrast, it showed antagonism, suggesting that CA could display interactions with Gem or DOX. To study the effect of CA and DOX on lung cancer • In vitro: mouse pulmonary system adenocarcinoma LA795 cell line • In vivo: Balb/c mice and Sprague Dawley (SD) rats In vitro: Not specified In vivo: CA (5.4 mg/kg bw) + DOX (4.1 mg/kg bw) In vitro: CA inhibited TMEM16A with an IC 50 of 29.47 ± 3.19 μM. CA regulated the proliferation, migration, and apoptosis of lung cancer cells targeting TMEM16A (binding sites: D439, E448, and R753). CA regulated the growth of lung cancer through the MAPK pathway. CA + DOX inhibited lung cancer cell growth more than a double dose of either one. In vivo: CA + DOX achieved a tumor suppression rate of 85.6% and compensated for side effects. To evaluate the effects of tocotrienols and CA encapsulated in a nanoemulsion with cisplatin on lung and liver cancer • In vivo: human lung cancer cell A549 and liver HEP G2 cancer cells. Not specified TRF, CA, and CIS synergistically enhanced late-phase apoptosis and improved cell cycle arrest in the G0/G1 phase. ROS generation was enhanced using TRF:CA:CIS by 16.9% and 30.2% for A549 and HEP G2, respectively. To evaluate the oxidative stress induced by multi-walled carbon nanotube (MWCNT) treatment on islets and β-cells. • In vivo: islets and β-cells CA significantly reduced ROS production after MWCNT treatment and increased insulin secretion together with the enzymes SOD, GSH-Px, CAT, and GSH, but it decreased the level of MDA. To evaluate the effect of CA encapsulated in a nanoemulsion on the reduction of nephrotoxicity effects • In vitro: non-cancer cells of the HEK 293 kidney line CA (0.08–1.75 μM) + CIS 0.03 μM Improved cell viability in kidney cells from 33% to over 95%. To evaluate delivery systems with CA for the treatment of breast cancer, loaded on oxidant carbon nanotube (OCNT) and/or chitosan (CS). • In vitro: human breast cancer MDA-MB-231 cell line CA (100 µg/mL); oxidant carbon nanotube (OCNT)/CA (80 µg/mL); and chitosan (CS)/OCNT/CA (30 µg/mL) The delivery system based on CS/OCNT/CA showed a higher cytotoxic effect on MDA-MB-231 compared to OCNT/CA and CA alone through apoptosis.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276737_p34
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|
9.2. Clinical Trials
| 3.839844 |
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|
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To assess the efficacy of CA in cancer therapy, we searched the clinical trial database clinicaltrials.gov using the keyword “caffeic acid”. One trial with the code NCT02050334, titled “CC100: Safety and Tolerability of Single Doses”, involved 18 participants aged 18 to 65. They were administered CA at a maximum concentration of 24 mg/kg. The findings indicated that CA did not lead to severe adverse effects; the main reported adverse effects were back pain and headache. However, the trial outcomes have not been published.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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9.2. Clinical Trials
| 4.195313 |
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The effectiveness and safety of CA were assessed in 103 patients with primary immune thrombocytopenia (ITP), with a median age of 48 years. They received an oral regimen of CA tablets at a dose of 300 mg three times per day for 12 weeks. The results demonstrated that CA treatment was effective, with minimal adverse effects, including mild nausea in one case and elevated liver enzymes in another . Furthermore, a meta-analysis involving 2533 patients indicated that CA is statistically effective in treating ITP, leading to an increase in platelet counts , with few adverse effects . However, other clinical trials, such as NCT04648917 (GASC1 Inhibitor Caffeic Acid for Squamous Esophageal Cell Cancer [ESCC]), NCT03070262 (The Efficacy and Safety of Caffeic Acid for Esophageal Cancer), and NCT02351622 (Caffeic Acid Tablets as a Second-line Therapy for ITP), have not published their results yet.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276737_p36
|
PMC11276737
|
sec[9]/p[0]
|
10. Radioprotective Potential of Caffeic Acid in Chemotherapy
| 4.035156 |
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|
Study
|
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Radiotherapy, a potent cytotoxic treatment, is widely utilized for localized solid tumors, either alone or in conjunction with chemotherapy . However, despite its efficacy, it also damages normal cells due to the minimal distinction between cancerous and healthy cells, particularly affecting skin cells, leading to adverse effects such as dermatological conditions and potential cancer development . Notably, nearly 95% of patients undergoing radiotherapy experience symptoms like pain, redness, or ulcers ; for instance, pelvic cancer treatment often results in damage to testicular tissue or neuropathy . Advanced techniques like intensity-modulated radiotherapy aim to mitigate these toxicities . Nonetheless, akin to chemotherapy, radiotherapy poses significant side effects that can substantially impact the quality of life of patients and treatment adherence . Table 4 outlines the protective effects of CA in conjunction with radiotherapy.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
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|
11. Conclusions
| 4.136719 |
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|
Study
|
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Further research is necessary to comprehensively ascertain the viability of CA as an anticancer treatment. However, preliminary clinical evidence suggests promising benefits. Studies conducted on cells and animals indicate that CA enhances the efficacy of chemotherapy and radiotherapy, potentially mitigating their adverse effects and improving patient outcomes with minimal side effects. This study has some limitations, including a lack of evidence for certain cancer types and omissions in many studies regarding whether the models are drug-resistant or simply aim to potentiate the action in non-resistant cancer cells. Additionally, in vivo testing is limited by small sample sizes, which may restrict the generalizability of the results. Cancer heterogeneity presents another significant limitation. Within a single tumor, cancer cells can vary significantly in differentiation, proliferation rate, metastatic capacity, and therapy susceptibility. This diversity can lead to subpopulations of cells responding differently to specific treatments . Consequently, in vitro models with a single cell type or minimal heterogeneity make it difficult to predict how a tumor with cells in varying degrees of neoplasia will behave. This variability implies that the adjuvant action of CA may differ considerably from patient to patient, even within the same cancer type. While a study may focus on a specific type, the results may not apply to other cases of the same cancer due to biological and molecular differences.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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sec[10]/p[1]
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11. Conclusions
| 4.035156 |
biomedical
|
Review
|
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0.0003917217254638672
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Another interesting property to continue studying is the dual capacity of CA to act as an antioxidant during carcinogenesis and as a pro-oxidant against cancer cells, promoting their apoptosis or sensitizing them to chemotherapeutic drugs. Future challenges include exploring different administration methods for CA as an adjuvant in therapies to treat different neoplasms. Some authors mention that CA’s chemical instability and limited bioavailability restrict its therapeutic potential in vivo. Currently, new formulations are being developed for CA administration in different pathologies, such as transferrin (Tf)-modified nanoparticles (NPs) loaded with CA for Alzheimer’s disease (AD) , topical cream with nanostructured lipid carriers (NLCs) loaded with CA for anti-inflammatory action , and poloxamer 407 designed to improve the stability of caffeic acid in the stomach . Nonetheless, the utilization of CA in cancer therapy requires more extensive investigation through clinical trials.
|
[
"Nicole Cortez",
"Cecilia Villegas",
"Viviana Burgos",
"Jaime R. Cabrera-Pardo",
"Leandro Ortiz",
"Iván González-Chavarría",
"Vaderament-A. Nchiozem-Ngnitedem",
"Cristian Paz"
] |
https://doi.org/10.3390/ijms25147631
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p0
|
PMC11276749
|
sec[0]/p[0]
|
1. Introduction
| 4.191406 |
biomedical
|
Review
|
[
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Gastric (or stomach) cancer (GC) is the sixth most frequently diagnosed and the third leading cause of cancer deaths worldwide. In 2020, over a million cases of GC were diagnosed, and the survival rate was notably low, resulting in 768,000 deaths . Several factors could contribute to the development of this devastating disease, such as Helicobacter pylori infection, smoking, or even obesity . In general, the treatment choice of GC patients is multimodal and involves pre- and postoperative chemotherapy. This strategy has demonstrated better outcomes compared to surgery alone . The perioperative FLOT (5-Fluorouracil, Oxaliplatin, and Docetaxel) regimen is the standard treatment in Europe for locally advanced GC, leading to better results than other approaches in terms of overall survival . However, despite its apparent success, this result may be misleading, as less than half of these patients were able to complete all eight cycles of the perioperative treatment due to toxicity issues . Moreover, resistance is another obstacle associated with classic chemotherapy, provoking clinical failures via tumor relapses. In light of these considerations, the discovery of new drugs that potentially avoid some of these clinical barriers is an obvious public healthcare priority.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p1
|
PMC11276749
|
sec[0]/p[1]
|
1. Introduction
| 4.101563 |
biomedical
|
Study
|
[
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0.00020742416381835938,
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[
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One of the possibilities lies in changing the metal center on the treatment molecule. There are numerous examples of new metal-based agents based in gold , palladium , copper , ruthenium , and iridium , among others. Even though none of these reported better outcomes in GC, platinum(II)-based drugs or their combinations are still leading to good results in research and therefore may have therapeutic potential . In fact, nowadays, the most effective clinical platinum drugs are still cisplatin-like derivatives with some structural differences to modulate their reactivity. The trans Pt(II) compounds were discarded at the early stages of development due to the lack of therapeutic activity of transplatin. However, it was later reported that in some cases, bulkier ligands binding around the Pt(II) center increased cytotoxicity. Our group reported some of these examples, highlighting the trans -[PtI 2 (isopropylamine) 2 ] called I5, which leads to great antitumor efficacy in mouse models, avoiding systemic toxicity .
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11276749_p2
|
PMC11276749
|
sec[0]/p[2]
|
1. Introduction
| 4.152344 |
biomedical
|
Study
|
[
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[
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The lipophilicity of the ligands coordinated to the Pt atom is a key factor that could favor the intracellular accumulation of the drug. Thus, the coordination of Pt(II) to a lipophilic and bulky ligand leads to a more robust structure, which improves stability, minimizing deactivation processes that could potentially limit the efficacy of the treatment We have reported a series of phosphine-based agents, containing triphenylphosphine ligand (-PPh 3 ) and a bulky amine in trans configuration, with a general formula trans -[Pt(amine)Cl 2 (PPh 3 )] . These compounds exhibited cytotoxic and pro-apoptotic activity (even higher than cisplatin (CDDP)) also against CDDP-resistant cancer cells . We also demonstrated the stability of these complexes at low concentrations in aqueous solutions (1% dimethyl sulfoxide (DMSO)) and using both experimental and computational protocols that allowed us to accurately characterize these complexes in solution.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p3
|
PMC11276749
|
sec[0]/p[3]
|
1. Introduction
| 4.101563 |
biomedical
|
Study
|
[
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] |
[
0.998046875,
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0.00007355213165283203
] |
As triphenylphosphine has been reported to be a mitochondrial targeting group and agents with this ligand are able to modulate mitochondrial metabolism , we wondered whether the cytotoxicity of our phosphine-based platinum complexes could be mainly due to mitochondrial dysfunction. There are different advantages in targeting mitochondria: (i) inhibiting cancer cell growth (due to the lack of energy); (ii) inducing apoptosis (via cytochrome C and caspases); (iii) bypassing the resistance associated with DNA repair mechanisms; and (iv) disrupting given metabolic processes .
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p4
|
PMC11276749
|
sec[0]/p[4]
|
1. Introduction
| 4.167969 |
biomedical
|
Study
|
[
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[
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In this paper, we have explored the mechanisms of action of two phosphine complexes: P1 ( trans -[PtCl 2 (dimethylamine)(PPh 3 )]) and P2 ( trans -[PtCl 2 (isopropylamine)(PPh 3 )]). We have measured their potential cytotoxicity in various gastro-intestinal tumor cell lines and in the non-tumoral Human Pancreatic Duct Epithelial (HPDE) cell line. We also included in our studies a healthy cell line from a different tissue, AC16 primary cardiomyocytes, to gauge the toxicity or specificity of these compounds in other tissues, specifically the heart, and finally conducted a further characterization analysis on GC cells. We have thoroughly evaluated mitochondrial status and Reactive Oxygen Species (ROS) generation, DNA damage, and endoplasmic reticulum (ER) stress. Altogether, the results we present here show a pivotal role for mitochondrial apoptosis in the mechanism of cell death that these complexes have shown to induce in cellulo.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276749_p5
|
PMC11276749
|
sec[1]/sec[0]/p[0]
|
2.1. Phospine-Based Agents P1 and P2 Decrease Cell Proliferation
| 4.125 |
biomedical
|
Study
|
[
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[
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We first assessed the cytotoxic effects of P1 and P2 on both tumoral (AGS, MKN45, and PANC1) and non-tumoral cell lines (AC16 and HPDE). To that end, cells were exposed to increasing concentrations (0–25 μM) of P1, P2, or CDDP for 48 h. The obtained IC 50 values ( Table 1 ) indicated that both complexes decreased cell viability in a dose-dependent manner , with P1 and P2 demonstrating greater activity in AGS tumoral cells compared to CDDP, a standard clinical treatment. Regarding selective indexes between gastrointestinal tumor cells and HPDE, it is noteworthy that non-tumoral cells exhibited lower sensitivity to the phosphine agents than to CDDP ( Table 1 ). In addition, P2 revealed higher cardiotoxicity than P1, but in both cases, lower than CDDP (see the selective indexes in Table S1 ).
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p6
|
PMC11276749
|
sec[1]/sec[0]/p[1]
|
2.1. Phospine-Based Agents P1 and P2 Decrease Cell Proliferation
| 4.082031 |
biomedical
|
Study
|
[
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[
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To further study the effect of our candidate agents on cell proliferation, we evaluated the impact of P1 and P2 on clonogenicity. The Colony Forming Unit (CFU) analysis revealed that both complexes inhibit proliferation at the IC 50 concentration or higher . We also observed that 3 h of treatment is enough to prevent colony formation, and this effect is still evident after removing the agent and maintaining the growth of cells for 10 days in a drug-free medium. This effect is similar to that of cells subjected to a maintained treatment over the course of 10 days . To evaluate if the effect on proliferation correlated with cell mobility processes, net, we studied cell migration after our treatment options but failed to detect any significant effect .
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11276749_p7
|
PMC11276749
|
sec[1]/sec[0]/p[2]
|
2.1. Phospine-Based Agents P1 and P2 Decrease Cell Proliferation
| 4.089844 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99951171875,
0.00016927719116210938,
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0.00005429983139038086
] |
Based on the results and before continuing with studies on the mechanism of action, we evaluated whether the cells had taken up the drugs. To do this, we quantified the concentration of platinum inside AGS cells treated with P1 and P2 (10 µM) for 3 h. We observed that after 3 h treatment, although platinum is found in both the nucleus and cytoplasm, both complexes preferentially accumulate in the cytoplasmatic fraction, with higher uptake observed in P2 samples ( Table 2 ).
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276749_p8
|
PMC11276749
|
sec[1]/sec[0]/p[3]
|
2.1. Phospine-Based Agents P1 and P2 Decrease Cell Proliferation
| 4.082031 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.99951171875,
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] |
We then analyzed the cell cycle profile after 24 h of treatment with P1 and P2 in AGS cells. We observed that both complexes, notably P2, induced apoptosis. Additionally, P2 slightly increased the percentage of cells in the S and G2/M phases more efficiently than P1 . These results indicate that none of the complexes affects cell mobility processes. However, both do interfere with GC cell viability and with proliferation.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276749_p9
|
PMC11276749
|
sec[1]/sec[1]/p[0]
|
2.2. P1 and P2 Generate ROS and Produce DNA Damage
| 4.160156 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99951171875,
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] |
Platinum complexes increase cellular ROS . Therefore, we aimed to investigate whether the phosphine-based agents generated ROS in vitro. We first quantified the levels of superoxide anions (O 2 •− ) in the cytosol of living cells (using Dihydroethidium (DHE) in AGS and MKN45 cells) and in mitochondria (using Mitosox in AGS cells) after 1 h of treatment with P1 (20 µM) and P2 (10 µM) but also with CDDP (20 µM) and H 2 O 2 (200 µM), which were used as positive controls. The signal obtained from our fluorescence indicator rapidly increased with both complexes, being slightly higher with P2, especially regarding mitochondrial ROS species . Subsequently, we investigated the GSH/GSSG system to further assess the redox status induced by P1 and P2. The higher presence of oxidized glutathione (GSSG) serves as an indicator of the presence of oxidant species that react with reduced glutathione (GSH). Thus, a lower GSH/GSSG ratio correlates with a higher ROS concentration in cells. We observed a decrease in this ratio after a 24 h treatment with both of our agents .
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11276749_p10
|
PMC11276749
|
sec[1]/sec[1]/p[1]
|
2.2. P1 and P2 Generate ROS and Produce DNA Damage
| 4.125 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99951171875,
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0.00005942583084106445
] |
To evaluate the influence of ROS on genotoxic stress, we analyzed the DNA double-stranded breaks in the AGS cells. The quantification of H2AX Ser139 positive nuclei showed that the number of foci per nucleus significantly increased 3 h after treatment (like CDDP) on a range of 20 to 40 foci per nuclei. Next, we evaluated the phosphorylation of p53 or CHK1 as markers of DNA damage response. While CDDP increased the activation of both, P1 and P2 only slightly activated these kinases .
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p11
|
PMC11276749
|
sec[1]/sec[1]/p[2]
|
2.2. P1 and P2 Generate ROS and Produce DNA Damage
| 4.0625 |
biomedical
|
Study
|
[
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[
0.9990234375,
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0.00006324052810668945
] |
These results suggest that, in GC cells, P1 and P2 are more effective than CDDP in generating ROS mainly in the mitochondria, which potentially leads to oxidative DNA damage.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276749_p12
|
PMC11276749
|
sec[1]/sec[2]/p[0]
|
2.3. P1 and P2 Target Mitochondria and Induce Apoptosis
| 4.109375 |
biomedical
|
Study
|
[
0.99951171875,
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[
0.99951171875,
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0.00005263090133666992
] |
Excessive levels of ROS in the mitochondria affect their membrane potential (ΔΨm). We studied the status of the mitochondria by measuring mitochondrial mass and ΔΨm in AGS cells exposed to CDDP, P1, and P2 (IC 50 concentration) for 2 h. Mitochondrial mass and ΔΨm were measured by using MitoTracker™ Green and MitoTracker™ Red CMXRos, respectively, and used to calculate the ΔΨm/Mit. Mass ratio, which allows the membrane potential respective to the total mitochondrial mass to be normalized . Our results show that CDDP, P1, and P2 decrease the ΔΨm/Mit. The mass ratio indicates the presence of dysfunctional mitochondria.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p13
|
PMC11276749
|
sec[1]/sec[2]/p[1]
|
2.3. P1 and P2 Target Mitochondria and Induce Apoptosis
| 4.144531 |
biomedical
|
Study
|
[
0.99951171875,
0.00028014183044433594,
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[
0.99951171875,
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Next, we studied the effect of the permeabilized mitochondria on the intrinsic apoptotic pathway after treatment with these complexes. We evaluated the expression of different BCL2 family member proteins: (i) pro-apoptotic—BAX, BAK, and BIM; (ii) anti-apoptotic—MCL1. All of the complexes (CDDP, P1, and P2) induced a reduction in MCL1 expression after 24 h. By contrast, CDDP and P2 treatment led to an increased BAK expression and only P2 significantly increased the levels of BIM, while P1 preferentially increased BAX expression . Altogether, these results underline mitochondrial apoptosis as a possible scenario of cell death elicited by these agents.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p14
|
PMC11276749
|
sec[1]/sec[3]/p[0]
|
2.4. P1 and P2 Produce ER Stress and Block Autophagy
| 4.3125 |
biomedical
|
Study
|
[
0.99951171875,
0.0003211498260498047,
0.00019824504852294922
] |
[
0.9990234375,
0.00023257732391357422,
0.0005564689636230469,
0.00008881092071533203
] |
The ER has emerged as a promising target for anticancer metallodrugs with redox activity . ROS induce protein misfolding, thus triggering the Unfolded Protein Response (UPR). Cells treated with CDDP, P1, and P2 were analyzed for a set of genes representative of each related pathway: PERK (EIF2AK3, ATF4, and C/EBP homologous protein (CHOP), encoded by the DDIT3 gene); IRE1α (ERN1 and XBP1); ATF6 (Activating Transcription Factor 6); and the common unfolded protein receptor from all three pathways, 78 kDa glucose-regulated protein (GRP78), encoded by the HSPA5 gene. The RT-PCR analysis revealed a robust induction of IRE1α and PERK-related genes in cells treated with P2, while no significant induction was observed after P1 treatment . To confirm protein induction, we analyzed by Western blotting GRP78, phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), CHOP, X-Box Binding Protein 1 (XBP1), and ATF6, all closely associated with ER stress and apoptosis. Our results confirmed that while all treatments induce the phosphorylation of eIF2α, only P2 leads to increased levels of all examined proteins (including the alternatively spliced form of XBP1), which is consistent with our qPCR findings .
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11276749_p15
|
PMC11276749
|
sec[1]/sec[3]/p[1]
|
2.4. P1 and P2 Produce ER Stress and Block Autophagy
| 4.167969 |
biomedical
|
Study
|
[
0.99951171875,
0.00028228759765625,
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] |
[
0.99951171875,
0.00017595291137695312,
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0.0000642538070678711
] |
Autophagy and UPR are activated in stressed cells in order to restore their cellular homeostasis. Consequently, we investigated the impact of P1 and P2 treatment on autophagy markers in AGS cells. To this end, we evaluated p62 and microtubule-associated protein 1 light chain 3 alpha (LC3-I and LC3-II) by Western blotting. LC3-I is a cytosolic form that, after activation by Atg7, is transferred to Atg3 and finally modified to LC3-II, the active membrane-bound form, typically located in the autophagosomes . The results from this set of experiments indicate that P2 influenced autophagy by increasing p62 and LC3-II . Finally, due to the known role of p62 in redox signaling after oxidative conditions, we sought to determine Nrf2 (nuclear factor erythroid 2-related factor 2) expression in our cells by Western blotting. Our blots showed that both P1 and P2 increase Nrf2 levels, with this increase being coupled to p62 accumulation .
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11276749_p16
|
PMC11276749
|
sec[2]/p[0]
|
3. Discussion
| 3.513672 |
biomedical
|
Other
|
[
0.99853515625,
0.000713348388671875,
0.0008373260498046875
] |
[
0.062042236328125,
0.73876953125,
0.1971435546875,
0.00214385986328125
] |
The approval of CDDP as an antitumor drug initiated a long search for new candidates with a potential to overcome the clinical challenges that limit CDDP-based chemotherapy. Carboplatin and oxaliplatin achieved the goal of being approved worldwide . The development of more effective drugs with less side effects is still a healthcare priority due to the high incidence and the elevated death rate associated to cancer diseases.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p17
|
PMC11276749
|
sec[2]/p[1]
|
3. Discussion
| 4.148438 |
biomedical
|
Study
|
[
0.99951171875,
0.0002779960632324219,
0.0002143383026123047
] |
[
0.99951171875,
0.00022995471954345703,
0.0002913475036621094,
0.00006008148193359375
] |
Phosphine-based platinum(II) complexes have gained attention due to the possibility of targeting mitochondria and the ability to overcome CDDP resistance . Herein, we start the preclinical stage studies of the prototypes trans -[PtCl 2 (dimethylamine)(PPh 3 )] (P1) and trans -[PtCl 2 (isopropylamine)(PPh 3 )] (P2) against GC. In our studies, we do find cytotoxic effects on gastrointestinal cancer cells, and we show that, at least in GC cells, this occurs through the intrinsic apoptotic pathway. However, while both P1 and P2 disrupt mitochondrial potential and generate ROS in GC cells, only P2 activates UPR, ER stress, and autophagy. This highlights the fact that their mechanism of action may differ, possibly due to differences in the chemical residues of both complexes.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11276749_p18
|
PMC11276749
|
sec[2]/p[2]
|
3. Discussion
| 4.089844 |
biomedical
|
Study
|
[
0.99951171875,
0.0002505779266357422,
0.0002199411392211914
] |
[
0.99951171875,
0.00018012523651123047,
0.0002884864807128906,
0.000057220458984375
] |
Our group has previously demonstrated the apoptotic effect of these compounds in ovarian cancer cell lines, either sensitive or resistant to CDDP (CH1 and CH1cisR) . Other studies with phosphorus donor ligands exhibit this capability to overcome CDDP resistance in breast cancer . Here, we document the impact of these compounds in GC cells. P2, which contains the bulkiest amine (isopropylamine), demonstrated the highest activity and cell uptake. Although in gastrointestinal healthy cells, both complexes exhibited less cytotoxicity than in cancer cells, other systemic toxicity issues (such us cardiotoxicity observed in AC16 cells) should be explored.
|
[
"Jorge Melones-Herrero",
"Patricia Delgado-Aliseda",
"Sofía Figueiras",
"Javier Velázquez-Gutiérrez",
"Adoración Gomez Quiroga",
"Carmela Calés",
"Isabel Sánchez-Pérez"
] |
https://doi.org/10.3390/ijms25147739
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
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