MP61-10 DNA METHYLATION INHIBITORS MAY REVERSE DRUG-RESISTANCE IN HUMAN BLADDER CANCER CELLS

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2016MP61-10 DNA METHYLATION INHIBITORS MAY REVERSE DRUG-RESISTANCE IN HUMAN BLADDER CANCER CELLS Naotaka Nishiyama, Stephanie Yi, Christopher E. Duymich, Siamak Daneshmand, Peter A. Jones, Hooman Djaladat, Naoya Masumori, and Gangning Liang Naotaka NishiyamaNaotaka Nishiyama More articles by this author , Stephanie YiStephanie Yi More articles by this author , Christopher E. DuymichChristopher E. Duymich More articles by this author , Siamak DaneshmandSiamak Daneshmand More articles by this author , Peter A. JonesPeter A. Jones More articles by this author , Hooman DjaladatHooman Djaladat More articles by this author , Naoya MasumoriNaoya Masumori More articles by this author , and Gangning LiangGangning Liang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.884AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Aberrant DNA methylation is among common events during tumorigenesis. Although heritable, the dynamic nature and its potential reversibility with pharmacological interventions make it an interesting target for drugs. The aim of this study was to evaluate the chemotherapeutic re-sensitivity of cisplatin (CDDP) and gemcitabine (GEM) resistance in bladder cancer cell lines induced by the hypomethylating agent 5-aza-2-deoxycytidine (5-Aza-CdR). METHODS Six bladder cancer cell lines, T24, UMUC3, T24-RCDDP, UMUC3-RCDDP, T24-RGEM and UMUC3-RGEM cells were used. The drug resistance cell lines, T24-RCDDP/UMUC3-RCDDP and T24-RGEM/UMUC3-RGEM, were newly established at our laboratory. Cell lines were treated with 1µM 5-Aza-CdR for 24 hours on day 1, with CDDP (5µg/ml) and GEM (30nmol/ml) on day 2, or combinatorial treatment of 5-Aza-CdR (day 1) and either CDDP or GEM (day 2). The cell phonotypical alterations were monitored by cell double time, DNA methylation changes and gene expression changes. RESULTS We used the Illumina Infinium Human Methylation450 BeadArray to measure the DNA methylation changes at 482,421 CpGs, and found dramatic DNA methylation alterations between T24 and UMUC3 bladder cancer cell lines, as well as their drug-resistance counterparts (T24-RCDDP/T24-RGEM and UMUC3-RCDDP/UMUC3-RGEM). We identified DNA hypermethylation at 28,271 and 45,927 CpG sites in T24 and UMUC3 drug resistant cells, respectively. Furthermore, we identified DNA hypomethylation at 41,576 and 18,711 CpG sites in T24 and UMUC3 drug resistant cells, respectively. In addition, 5-Aza-CdR may re-sensitize CDDP-resistant cell lines, since the cell double time significantly increased from 70 (T24-RCDDP) or 86 (UMUC3-RCDDP) hours by CDDP alone to 495 (T24-RCDDP) or 721(UMUC3-RCDDP) hours after the combination treatments. However, it should be noted that the combination treatment of 5-Aza-CdR with GEM did not re-sensitize the chemotherapeutic effect on GEM-resistant cells. CONCLUSIONS Overall, our results indicate that alteration of DNA methylation may play an important role in drug-resistance, while DNA methylation re-programming may also sensitize the chemotherapeutic efficacy for drug resistance cells especially in metastatic urothelial carcinoma. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e806-e807 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Naotaka Nishiyama More articles by this author Stephanie Yi More articles by this author Christopher E. Duymich More articles by this author Siamak Daneshmand More articles by this author Peter A. Jones More articles by this author Hooman Djaladat More articles by this author Naoya Masumori More articles by this author Gangning Liang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...