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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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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fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2642459077</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2642459077</sourcerecordid><originalsourceid>FETCH-LOGICAL-c295t-cfff3a1a0def8d809577f67882f7a29dc0baae726e1df42e270af02bad04e6823</originalsourceid><addsrcrecordid>eNpNkEFLw0AQhRdRsGgv_oIBb0J0s5tkN8cQalus2EM9h2l2l2xNdusmVerJn25LBX2XeQ--mYFHyE1M7znP6cM2xJRymiTyjIwYYyLKRSzO__lLMu77DT0oj7lMsxH5nmLb2hqK2iqYuAZdrXsYGg2FG2xUHnOAiTG6HsAbWOnOf_nWd1ZpsA5muw4dTFvrO4RSty0srNPwYRHmrrFrO1jvjovF2wDoFGy5jJ6L5RMscWg-cX9NLgy2vR7_zivy-jhZlbNo8TKdl8UiqlmeDlFtjOEYI1XaSCVpngphMiElMwJZrmq6RtSCZTpWJmGaCYqGsjUqmuhMMn5Fbk93t8G_73Q_VBu_C-7wsmJZwpI0p0IcqLsTVQff90Gbahtsh2FfxbQ6llz9lcx_ANRcbfs</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2642459077</pqid></control><display><type>article</type><title>Gallic Acid Enhances the Anti-Cancer Effect of Temozolomide in Human Glioma Cell Line via Inhibition of Akt and p38-MAPK Pathway</title><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>EZB-FREE-00999 freely available EZB journals</source><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</creator><creatorcontrib>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</creatorcontrib><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><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&D ; Reactive oxygen species ; Research & 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&D</subject><subject>Reactive oxygen species</subject><subject>Research & development</subject><subject>Temozolomide</subject><subject>Western blotting</subject><issn>2227-9717</issn><issn>2227-9717</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpNkEFLw0AQhRdRsGgv_oIBb0J0s5tkN8cQalus2EM9h2l2l2xNdusmVerJn25LBX2XeQ--mYFHyE1M7znP6cM2xJRymiTyjIwYYyLKRSzO__lLMu77DT0oj7lMsxH5nmLb2hqK2iqYuAZdrXsYGg2FG2xUHnOAiTG6HsAbWOnOf_nWd1ZpsA5muw4dTFvrO4RSty0srNPwYRHmrrFrO1jvjovF2wDoFGy5jJ6L5RMscWg-cX9NLgy2vR7_zivy-jhZlbNo8TKdl8UiqlmeDlFtjOEYI1XaSCVpngphMiElMwJZrmq6RtSCZTpWJmGaCYqGsjUqmuhMMn5Fbk93t8G_73Q_VBu_C-7wsmJZwpI0p0IcqLsTVQff90Gbahtsh2FfxbQ6llz9lcx_ANRcbfs</recordid><startdate>20220301</startdate><enddate>20220301</enddate><creator>Yang, Jen-Tsung</creator><creator>Lee, I-Neng</creator><creator>Chen, Chun-Han</creator><creator>Lu, Fung-Jou</creator><creator>Chung, Chiu-Yen</creator><creator>Lee, Ming-Hsueh</creator><creator>Cheng, Yu-Ching</creator><creator>Chen, Kuo-Tai</creator><creator>Peng, Jyun-Yu</creator><creator>Chen, Ching-Hsein</creator><general>MDPI AG</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>JG9</scope><scope>KB.</scope><scope>LK8</scope><scope>M7P</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><orcidid>https://orcid.org/0000-0003-0578-7116</orcidid><orcidid>https://orcid.org/0000-0001-5341-7764</orcidid></search><sort><creationdate>20220301</creationdate><title>Gallic Acid Enhances the Anti-Cancer Effect of Temozolomide in Human Glioma Cell Line via Inhibition of Akt and p38-MAPK Pathway</title><author>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</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&D</topic><topic>Reactive oxygen species</topic><topic>Research & development</topic><topic>Temozolomide</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><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><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>Materials Research Database</collection><collection>Materials Science Database</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><jtitle>Processes</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Jen-Tsung</au><au>Lee, I-Neng</au><au>Chen, Chun-Han</au><au>Lu, Fung-Jou</au><au>Chung, Chiu-Yen</au><au>Lee, Ming-Hsueh</au><au>Cheng, Yu-Ching</au><au>Chen, Kuo-Tai</au><au>Peng, Jyun-Yu</au><au>Chen, Ching-Hsein</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gallic Acid Enhances the Anti-Cancer Effect of Temozolomide in Human Glioma Cell Line via Inhibition of Akt and p38-MAPK Pathway</atitle><jtitle>Processes</jtitle><date>2022-03-01</date><risdate>2022</risdate><volume>10</volume><issue>3</issue><spage>448</spage><pages>448-</pages><issn>2227-9717</issn><eissn>2227-9717</eissn><abstract>(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.</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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