GSTP1 DNA methylation and expression status is indicative of 5-aza-2'-deoxycytidine efficacy in human prostate cancer cells
DNA methylation plays an important role in carcinogenesis and the reversibility of this epigenetic modification makes it a potential therapeutic target. To date, DNA methyltransferase inhibitors (DNMTi) have not demonstrated clinical efficacy in prostate cancer, with one of the major obstacles being...
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| description | DNA methylation plays an important role in carcinogenesis and the reversibility of this epigenetic modification makes it a potential therapeutic target. To date, DNA methyltransferase inhibitors (DNMTi) have not demonstrated clinical efficacy in prostate cancer, with one of the major obstacles being the inability to monitor drug activity during the trial. Given the high frequency and specificity of GSTP1 DNA methylation in prostate cancer, we investigated whether GSTP1 is a useful marker of DNMTi treatment efficacy. LNCaP prostate cancer cells were treated with 5-aza-2'-deoxycytidine (5-aza-CdR) either with a single high dose (5-20 µM), every alternate day (0.1-10 µM) or daily (0.005-2.5 µM). A daily treatment regimen with 5-aza-CdR was optimal, with significant suppression of cell proliferation achieved with doses of 0.05 µM or greater (p |
| doi_str_mv | 10.1371/journal.pone.0025634 |
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To date, DNA methyltransferase inhibitors (DNMTi) have not demonstrated clinical efficacy in prostate cancer, with one of the major obstacles being the inability to monitor drug activity during the trial. Given the high frequency and specificity of GSTP1 DNA methylation in prostate cancer, we investigated whether GSTP1 is a useful marker of DNMTi treatment efficacy. LNCaP prostate cancer cells were treated with 5-aza-2'-deoxycytidine (5-aza-CdR) either with a single high dose (5-20 µM), every alternate day (0.1-10 µM) or daily (0.005-2.5 µM). A daily treatment regimen with 5-aza-CdR was optimal, with significant suppression of cell proliferation achieved with doses of 0.05 µM or greater (p<0.0001) and induction of cell death from 0.5 µM (p<0.0001). In contrast, treatment with a single high dose of 20 µM 5-aza-CdR inhibited cell proliferation but was not able to induce cell death. Demethylation of GSTP1 was observed with doses of 5-aza-CdR that induced significant suppression of cell proliferation (≥ 0.05 µM). Re-expression of the GSTP1 protein was observed only at doses of 5-aza-CdR (≥ 0.5 µM) associated with induction of cell death. Treatment of LNCaP cells with a more stable DNMTi, Zebularine required at least a 100-fold higher dose (≥ 50 µM) to inhibit proliferation and was less potent in inducing cell death, which corresponded to a lack of GSTP1 protein re-expression. We have shown that GSTP1 DNA methylation and protein expression status is correlated with DNMTi treatment response in prostate cancer cells. Since GSTP1 is methylated in nearly all prostate cancers, our results warrant its testing as a marker of epigenetic therapy response in future clinical trials. We conclude that the DNA methylation and protein expression status of GSTP1 are good indicators of DNMTi efficacy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0025634</identifier><identifier>PMID: 21980513</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Androgens ; Azacitidine - adverse effects ; Azacitidine - analogs & derivatives ; Azacitidine - pharmacology ; Biology ; Biomarkers, Tumor - deficiency ; Biomarkers, Tumor - genetics ; Cancer ; Cancer cells ; Cancer genetics ; Carcinogenesis ; Carcinogens ; Cell death ; Cell Death - drug effects ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Clinical trials ; Cytidine - analogs & derivatives ; Cytidine - pharmacology ; Demethylation ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA Methylation - drug effects ; DNA methyltransferase ; Dose-Response Relationship, Drug ; Drug Discovery ; Drug therapy ; Effectiveness ; Enzyme Inhibitors - adverse effects ; Enzyme Inhibitors - pharmacology ; Epigenetic inheritance ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Silencing - drug effects ; Glutathione S-Transferase pi - deficiency ; Glutathione S-Transferase pi - genetics ; Glutathione transferase ; Health aspects ; Humans ; Male ; Medical research ; Medicine ; Methylation ; Mortality ; Promoter Regions, Genetic - drug effects ; Promoter Regions, Genetic - genetics ; Prostate cancer ; Prostate-Specific Antigen - blood ; Prostatic Neoplasms - blood ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; Studies ; Time Factors</subject><ispartof>PloS one, 2011-09, Vol.6 (9), p.e25634</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Chiam et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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To date, DNA methyltransferase inhibitors (DNMTi) have not demonstrated clinical efficacy in prostate cancer, with one of the major obstacles being the inability to monitor drug activity during the trial. Given the high frequency and specificity of GSTP1 DNA methylation in prostate cancer, we investigated whether GSTP1 is a useful marker of DNMTi treatment efficacy. LNCaP prostate cancer cells were treated with 5-aza-2'-deoxycytidine (5-aza-CdR) either with a single high dose (5-20 µM), every alternate day (0.1-10 µM) or daily (0.005-2.5 µM). A daily treatment regimen with 5-aza-CdR was optimal, with significant suppression of cell proliferation achieved with doses of 0.05 µM or greater (p<0.0001) and induction of cell death from 0.5 µM (p<0.0001). In contrast, treatment with a single high dose of 20 µM 5-aza-CdR inhibited cell proliferation but was not able to induce cell death. Demethylation of GSTP1 was observed with doses of 5-aza-CdR that induced significant suppression of cell proliferation (≥ 0.05 µM). Re-expression of the GSTP1 protein was observed only at doses of 5-aza-CdR (≥ 0.5 µM) associated with induction of cell death. Treatment of LNCaP cells with a more stable DNMTi, Zebularine required at least a 100-fold higher dose (≥ 50 µM) to inhibit proliferation and was less potent in inducing cell death, which corresponded to a lack of GSTP1 protein re-expression. We have shown that GSTP1 DNA methylation and protein expression status is correlated with DNMTi treatment response in prostate cancer cells. Since GSTP1 is methylated in nearly all prostate cancers, our results warrant its testing as a marker of epigenetic therapy response in future clinical trials. 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drug effects</subject><subject>DNA methyltransferase</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Drug therapy</subject><subject>Effectiveness</subject><subject>Enzyme Inhibitors - adverse effects</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Epigenetic inheritance</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Silencing - drug effects</subject><subject>Glutathione S-Transferase pi - deficiency</subject><subject>Glutathione S-Transferase pi - genetics</subject><subject>Glutathione transferase</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Methylation</subject><subject>Mortality</subject><subject>Promoter Regions, Genetic - drug effects</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Prostate cancer</subject><subject>Prostate-Specific Antigen - 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To date, DNA methyltransferase inhibitors (DNMTi) have not demonstrated clinical efficacy in prostate cancer, with one of the major obstacles being the inability to monitor drug activity during the trial. Given the high frequency and specificity of GSTP1 DNA methylation in prostate cancer, we investigated whether GSTP1 is a useful marker of DNMTi treatment efficacy. LNCaP prostate cancer cells were treated with 5-aza-2'-deoxycytidine (5-aza-CdR) either with a single high dose (5-20 µM), every alternate day (0.1-10 µM) or daily (0.005-2.5 µM). A daily treatment regimen with 5-aza-CdR was optimal, with significant suppression of cell proliferation achieved with doses of 0.05 µM or greater (p<0.0001) and induction of cell death from 0.5 µM (p<0.0001). In contrast, treatment with a single high dose of 20 µM 5-aza-CdR inhibited cell proliferation but was not able to induce cell death. Demethylation of GSTP1 was observed with doses of 5-aza-CdR that induced significant suppression of cell proliferation (≥ 0.05 µM). Re-expression of the GSTP1 protein was observed only at doses of 5-aza-CdR (≥ 0.5 µM) associated with induction of cell death. Treatment of LNCaP cells with a more stable DNMTi, Zebularine required at least a 100-fold higher dose (≥ 50 µM) to inhibit proliferation and was less potent in inducing cell death, which corresponded to a lack of GSTP1 protein re-expression. We have shown that GSTP1 DNA methylation and protein expression status is correlated with DNMTi treatment response in prostate cancer cells. Since GSTP1 is methylated in nearly all prostate cancers, our results warrant its testing as a marker of epigenetic therapy response in future clinical trials. We conclude that the DNA methylation and protein expression status of GSTP1 are good indicators of DNMTi efficacy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21980513</pmid><doi>10.1371/journal.pone.0025634</doi><tpages>e25634</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1308857995 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Androgens Azacitidine - adverse effects Azacitidine - analogs & derivatives Azacitidine - pharmacology Biology Biomarkers, Tumor - deficiency Biomarkers, Tumor - genetics Cancer Cancer cells Cancer genetics Carcinogenesis Carcinogens Cell death Cell Death - drug effects Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cell Survival - drug effects Clinical trials Cytidine - analogs & derivatives Cytidine - pharmacology Demethylation Deoxyribonucleic acid DNA DNA methylation DNA Methylation - drug effects DNA methyltransferase Dose-Response Relationship, Drug Drug Discovery Drug therapy Effectiveness Enzyme Inhibitors - adverse effects Enzyme Inhibitors - pharmacology Epigenetic inheritance Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene Silencing - drug effects Glutathione S-Transferase pi - deficiency Glutathione S-Transferase pi - genetics Glutathione transferase Health aspects Humans Male Medical research Medicine Methylation Mortality Promoter Regions, Genetic - drug effects Promoter Regions, Genetic - genetics Prostate cancer Prostate-Specific Antigen - blood Prostatic Neoplasms - blood Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Studies Time Factors |
| title | GSTP1 DNA methylation and expression status is indicative of 5-aza-2'-deoxycytidine efficacy in human prostate cancer cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-14T23%3A40%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=GSTP1%20DNA%20methylation%20and%20expression%20status%20is%20indicative%20of%205-aza-2'-deoxycytidine%20efficacy%20in%20human%20prostate%20cancer%20cells&rft.jtitle=PloS%20one&rft.au=Chiam,%20Karen&rft.date=2011-09-28&rft.volume=6&rft.issue=9&rft.spage=e25634&rft.pages=e25634-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0025634&rft_dat=%3Cgale_plos_%3EA476877542%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1308857995&rft_id=info:pmid/21980513&rft_galeid=A476877542&rft_doaj_id=oai_doaj_org_article_ac069471b82840efafe51910a383c3b8&rfr_iscdi=true |