MP84-20 BIOINFORMATIC ANALYSIS UTILIZING THE ANDROGENIC SUPPRESSIVE EFFECT IDENTIFIED PROMISING CANDIDATE DRUGS FOR REPROGRAMMING DOCETAXEL-RESISTANT CASTRATION-RESISTANT PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III1 Apr 2016MP84-20 BIOINFORMATIC ANALYSIS UTILIZING THE ANDROGENIC SUPPRESSIVE EFFECT IDENTIFIED PROMISING CANDIDATE DRUGS FOR REPROGRAMMING DOCETAXEL-RESISTANT CASTRATION-RESISTANT PROSTATE CANCER Hiroshi Hongo, Takeo Kosaka, Yota Yasumizu, Yasumasa Miyazaki, Eiji Kikuchi, Akira Miyajima, and Mototsugu Oya Hiroshi HongoHiroshi Hongo More articles by this author , Takeo KosakaTakeo Kosaka More articles by this author , Yota YasumizuYota Yasumizu More articles by this author , Yasumasa MiyazakiYasumasa Miyazaki More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , Akira MiyajimaAkira Miyajima More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2244AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recent evidence suggests CRPC cells may have an unknown regulation system to protect themselves from the androgenic suppressive effect. In this study, we investigated gene expression profiles of androgen-treated cells using a whole human genome microarray, and identified candidate drugs for reprogramming of docetaxel-resistant castration-resistant prostate cancer. METHODS Two cell lines were used: LNCaP and C4-2AT6, a castration-resistant prostate cancer cell line. Gene expression profiles of androgen-treated cells were analyzed and compared using CMAP to identify candidate drugs with the potential to revert an inverse gene signature pattern. RESULTS We investigated and compared the viability of prostate cancer cells treated with DHT at various concentrations. When treated with 0.1 nM DHT, LNCaP cells demonstrated significantly increased cell viability. On the other hand, C4-2AT6 cells showed significantly decreased cell viability when treated with 0.1 nM DHT. We next investigated and compared the gene signatures between LNCaP and C4-2AT6 cells treated with 0.1 nM DHT. CMAP analysis identified candidate drugs for reprogramming the gene expression changes. Based on the CMAP analysis data, candidate drugs were screened and tested for anti-tumor activity. The cytotoxic effect of docetaxel was first investigated by a cell viability assay in LNCaP and C4-2AT6 cells; relative cell viability when treated with 1nM docetaxel was 48.8 ± 0.1 % and 87.5 ± 1.9 %, respectively, suggesting increased docetaxel resistance in C4-2AT6 cells. Among the listed drugs, KOSH035 was identified as a candidate for reprogramming the castration resistance of docetaxel-resistant C4-2AT6 cells. We investigated the anti-tumor activity of KOSH035 on LNCaP and C4-2AT6 cells, and observed that relative cell viability was 72.2 ± 1.2 % and 72.8 ± 4.4 %, respectively. We further investigated the synergic effect of docetaxel and KOSH035. Relative cell viabilities of LNCaP and C4-2AT6 cells after treatment with both 1nM docetaxel and 10uM KOSH035 were 51.4 ± 0.5 % and 68.1 ± 2.0 %, respectively. The combination of docetaxel and KOSH035 showed a synergic effect on CRPC cells. CONCLUSIONS KOSH035 may be promising drug for reprogramming docetaxel-resistant PC. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1097 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Hiroshi Hongo More articles by this author Takeo Kosaka More articles by this author Yota Yasumizu More articles by this author Yasumasa Miyazaki More articles by this author Eiji Kikuchi More articles by this author Akira Miyajima More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...