Gallic Acid Enhances the Anti-Cancer Effect of Temozolomide in Human Glioma Cell Line via Inhibition of Akt and p38-MAPK Pathway

(1) Background: Temozolomide (TMZ), an oral alkylating agent, is used to treat malignant gliomas and other difficult-to-treat tumors. TMZ can enter the cerebrospinal fluid p.o. (per os) and does not need hepatic metabolism for activation of its use as a standard chemotherapeutic regimen after surgic...

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Veröffentlicht in:Processes 2022-03, Vol.10 (3), p.448
Hauptverfasser: Yang, Jen-Tsung, Lee, I-Neng, Chen, Chun-Han, Lu, Fung-Jou, Chung, Chiu-Yen, Lee, Ming-Hsueh, Cheng, Yu-Ching, Chen, Kuo-Tai, Peng, Jyun-Yu, Chen, Ching-Hsein
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container_issue 3
container_start_page 448
container_title Processes
container_volume 10
creator Yang, Jen-Tsung
Lee, I-Neng
Chen, Chun-Han
Lu, Fung-Jou
Chung, Chiu-Yen
Lee, Ming-Hsueh
Cheng, Yu-Ching
Chen, Kuo-Tai
Peng, Jyun-Yu
Chen, Ching-Hsein
description (1) Background: Temozolomide (TMZ), an oral alkylating agent, is used to treat malignant gliomas and other difficult-to-treat tumors. TMZ can enter the cerebrospinal fluid p.o. (per os) and does not need hepatic metabolism for activation of its use as a standard chemotherapeutic regimen after surgical resection of malignant glioma of the brain. However, the prognosis remains poor for most patients, and the survival rate is still unsatisfactory. Gallic acid (Ga) is a secondary metabolite existent in numerous plants. Ga shows various bioactivities, including antioxidant, anti-inflammatory, anticancer and antimicrobial effects. In this study, the latent enhanced anti-cancer efficacy of Ga in TMZ-treated U87MG cells (a human glioma line) was evaluated. (2) Methods: The U87MG cell line was cultured for 24 h. The cells were incubated with Ga alone, TMZ alone, or their combination for various time points. Cell viability and the drug combination index were evaluated by an XTT-based analysis and isobologram analysis, respectively. DNA destruction and intracellular reactive oxygen species (ROS) generation were analyzed by flow cytometer. The expression of various proteins was assessed via Western blotting. (3) Results: Compared with the action of TMZ alone or Ga alone, TMZ/Ga combination augmented the inhibition of cellular viability and apoptotic level in the U87MG glioma cell line. This enhanced anti-cancer effect correlated with the decreased expression of Bcl-2 and p-Akt, and corresponded with the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. In addition, Ga suppressed the TMZ-promoted ROS generation. (4) Conclusions: Ga can augment the anti-cancer effect of TMZ via the repression of Bcl-2 expression and Akt activation and the enhancement of the p38 MAPK pathway. Our results offer a novel probable approach for the medical treatment of malignant glioma.
doi_str_mv 10.3390/pr10030448
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TMZ can enter the cerebrospinal fluid p.o. (per os) and does not need hepatic metabolism for activation of its use as a standard chemotherapeutic regimen after surgical resection of malignant glioma of the brain. However, the prognosis remains poor for most patients, and the survival rate is still unsatisfactory. Gallic acid (Ga) is a secondary metabolite existent in numerous plants. Ga shows various bioactivities, including antioxidant, anti-inflammatory, anticancer and antimicrobial effects. In this study, the latent enhanced anti-cancer efficacy of Ga in TMZ-treated U87MG cells (a human glioma line) was evaluated. (2) Methods: The U87MG cell line was cultured for 24 h. The cells were incubated with Ga alone, TMZ alone, or their combination for various time points. Cell viability and the drug combination index were evaluated by an XTT-based analysis and isobologram analysis, respectively. DNA destruction and intracellular reactive oxygen species (ROS) generation were analyzed by flow cytometer. The expression of various proteins was assessed via Western blotting. (3) Results: Compared with the action of TMZ alone or Ga alone, TMZ/Ga combination augmented the inhibition of cellular viability and apoptotic level in the U87MG glioma cell line. This enhanced anti-cancer effect correlated with the decreased expression of Bcl-2 and p-Akt, and corresponded with the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. In addition, Ga suppressed the TMZ-promoted ROS generation. (4) Conclusions: Ga can augment the anti-cancer effect of TMZ via the repression of Bcl-2 expression and Akt activation and the enhancement of the p38 MAPK pathway. Our results offer a novel probable approach for the medical treatment of malignant glioma.</description><identifier>ISSN: 2227-9717</identifier><identifier>EISSN: 2227-9717</identifier><identifier>DOI: 10.3390/pr10030448</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>AKT protein ; Alkylation ; Antibodies ; Anticancer properties ; Antiinfectives and antibacterials ; Antioxidants ; Apoptosis ; Bcl-2 protein ; Biotechnology ; Brain research ; Brain tumors ; Cancer ; Cell viability ; Cerebrospinal fluid ; Drug dosages ; Evaluation ; Fluorides ; Gallic acid ; Glioma cells ; Inflammation ; Kinases ; MAP kinase ; Medical treatment ; Metabolites ; Protein kinase ; Proteins ; R&amp;D ; Reactive oxygen species ; Research &amp; development ; Temozolomide ; Western blotting</subject><ispartof>Processes, 2022-03, Vol.10 (3), p.448</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c295t-cfff3a1a0def8d809577f67882f7a29dc0baae726e1df42e270af02bad04e6823</citedby><cites>FETCH-LOGICAL-c295t-cfff3a1a0def8d809577f67882f7a29dc0baae726e1df42e270af02bad04e6823</cites><orcidid>0000-0003-0578-7116 ; 0000-0001-5341-7764</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids></links><search><creatorcontrib>Yang, Jen-Tsung</creatorcontrib><creatorcontrib>Lee, I-Neng</creatorcontrib><creatorcontrib>Chen, Chun-Han</creatorcontrib><creatorcontrib>Lu, Fung-Jou</creatorcontrib><creatorcontrib>Chung, Chiu-Yen</creatorcontrib><creatorcontrib>Lee, Ming-Hsueh</creatorcontrib><creatorcontrib>Cheng, Yu-Ching</creatorcontrib><creatorcontrib>Chen, Kuo-Tai</creatorcontrib><creatorcontrib>Peng, Jyun-Yu</creatorcontrib><creatorcontrib>Chen, Ching-Hsein</creatorcontrib><title>Gallic Acid Enhances the Anti-Cancer Effect of Temozolomide in Human Glioma Cell Line via Inhibition of Akt and p38-MAPK Pathway</title><title>Processes</title><description>(1) Background: Temozolomide (TMZ), an oral alkylating agent, is used to treat malignant gliomas and other difficult-to-treat tumors. TMZ can enter the cerebrospinal fluid p.o. (per os) and does not need hepatic metabolism for activation of its use as a standard chemotherapeutic regimen after surgical resection of malignant glioma of the brain. However, the prognosis remains poor for most patients, and the survival rate is still unsatisfactory. Gallic acid (Ga) is a secondary metabolite existent in numerous plants. Ga shows various bioactivities, including antioxidant, anti-inflammatory, anticancer and antimicrobial effects. In this study, the latent enhanced anti-cancer efficacy of Ga in TMZ-treated U87MG cells (a human glioma line) was evaluated. (2) Methods: The U87MG cell line was cultured for 24 h. The cells were incubated with Ga alone, TMZ alone, or their combination for various time points. Cell viability and the drug combination index were evaluated by an XTT-based analysis and isobologram analysis, respectively. DNA destruction and intracellular reactive oxygen species (ROS) generation were analyzed by flow cytometer. The expression of various proteins was assessed via Western blotting. (3) Results: Compared with the action of TMZ alone or Ga alone, TMZ/Ga combination augmented the inhibition of cellular viability and apoptotic level in the U87MG glioma cell line. This enhanced anti-cancer effect correlated with the decreased expression of Bcl-2 and p-Akt, and corresponded with the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. In addition, Ga suppressed the TMZ-promoted ROS generation. (4) Conclusions: Ga can augment the anti-cancer effect of TMZ via the repression of Bcl-2 expression and Akt activation and the enhancement of the p38 MAPK pathway. Our results offer a novel probable approach for the medical treatment of malignant glioma.</description><subject>AKT protein</subject><subject>Alkylation</subject><subject>Antibodies</subject><subject>Anticancer properties</subject><subject>Antiinfectives and antibacterials</subject><subject>Antioxidants</subject><subject>Apoptosis</subject><subject>Bcl-2 protein</subject><subject>Biotechnology</subject><subject>Brain research</subject><subject>Brain tumors</subject><subject>Cancer</subject><subject>Cell viability</subject><subject>Cerebrospinal fluid</subject><subject>Drug dosages</subject><subject>Evaluation</subject><subject>Fluorides</subject><subject>Gallic acid</subject><subject>Glioma cells</subject><subject>Inflammation</subject><subject>Kinases</subject><subject>MAP kinase</subject><subject>Medical treatment</subject><subject>Metabolites</subject><subject>Protein kinase</subject><subject>Proteins</subject><subject>R&amp;D</subject><subject>Reactive oxygen species</subject><subject>Research &amp; 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Lee, I-Neng ; Chen, Chun-Han ; Lu, Fung-Jou ; Chung, Chiu-Yen ; Lee, Ming-Hsueh ; Cheng, Yu-Ching ; Chen, Kuo-Tai ; Peng, Jyun-Yu ; Chen, Ching-Hsein</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c295t-cfff3a1a0def8d809577f67882f7a29dc0baae726e1df42e270af02bad04e6823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>AKT protein</topic><topic>Alkylation</topic><topic>Antibodies</topic><topic>Anticancer properties</topic><topic>Antiinfectives and antibacterials</topic><topic>Antioxidants</topic><topic>Apoptosis</topic><topic>Bcl-2 protein</topic><topic>Biotechnology</topic><topic>Brain research</topic><topic>Brain tumors</topic><topic>Cancer</topic><topic>Cell viability</topic><topic>Cerebrospinal fluid</topic><topic>Drug dosages</topic><topic>Evaluation</topic><topic>Fluorides</topic><topic>Gallic acid</topic><topic>Glioma cells</topic><topic>Inflammation</topic><topic>Kinases</topic><topic>MAP kinase</topic><topic>Medical treatment</topic><topic>Metabolites</topic><topic>Protein kinase</topic><topic>Proteins</topic><topic>R&amp;D</topic><topic>Reactive oxygen species</topic><topic>Research &amp; 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TMZ can enter the cerebrospinal fluid p.o. (per os) and does not need hepatic metabolism for activation of its use as a standard chemotherapeutic regimen after surgical resection of malignant glioma of the brain. However, the prognosis remains poor for most patients, and the survival rate is still unsatisfactory. Gallic acid (Ga) is a secondary metabolite existent in numerous plants. Ga shows various bioactivities, including antioxidant, anti-inflammatory, anticancer and antimicrobial effects. In this study, the latent enhanced anti-cancer efficacy of Ga in TMZ-treated U87MG cells (a human glioma line) was evaluated. (2) Methods: The U87MG cell line was cultured for 24 h. The cells were incubated with Ga alone, TMZ alone, or their combination for various time points. Cell viability and the drug combination index were evaluated by an XTT-based analysis and isobologram analysis, respectively. DNA destruction and intracellular reactive oxygen species (ROS) generation were analyzed by flow cytometer. The expression of various proteins was assessed via Western blotting. (3) Results: Compared with the action of TMZ alone or Ga alone, TMZ/Ga combination augmented the inhibition of cellular viability and apoptotic level in the U87MG glioma cell line. This enhanced anti-cancer effect correlated with the decreased expression of Bcl-2 and p-Akt, and corresponded with the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. In addition, Ga suppressed the TMZ-promoted ROS generation. (4) Conclusions: Ga can augment the anti-cancer effect of TMZ via the repression of Bcl-2 expression and Akt activation and the enhancement of the p38 MAPK pathway. Our results offer a novel probable approach for the medical treatment of malignant glioma.</abstract><cop>Basel</cop><pub>MDPI AG</pub><doi>10.3390/pr10030448</doi><orcidid>https://orcid.org/0000-0003-0578-7116</orcidid><orcidid>https://orcid.org/0000-0001-5341-7764</orcidid><oa>free_for_read</oa></addata></record>
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subjects AKT protein
Alkylation
Antibodies
Anticancer properties
Antiinfectives and antibacterials
Antioxidants
Apoptosis
Bcl-2 protein
Biotechnology
Brain research
Brain tumors
Cancer
Cell viability
Cerebrospinal fluid
Drug dosages
Evaluation
Fluorides
Gallic acid
Glioma cells
Inflammation
Kinases
MAP kinase
Medical treatment
Metabolites
Protein kinase
Proteins
R&D
Reactive oxygen species
Research & development
Temozolomide
Western blotting
title Gallic Acid Enhances the Anti-Cancer Effect of Temozolomide in Human Glioma Cell Line via Inhibition of Akt and p38-MAPK Pathway
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