MP83-08 COMBINATION OF METFORMIN AND SODIUM VALPROATE FOR PROSTATE CANCER: A RAPID APPROACH FROM BENCH TO CLINICAL TRIAL.

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II1 Apr 2017MP83-08 COMBINATION OF METFORMIN AND SODIUM VALPROATE FOR PROSTATE CANCER: A RAPID APPROACH FROM BENCH TO CLINICAL TRIAL. Linh N.K. Tran, Ganessan Kichenadasse, Rebecca J. Ormsby, Katherine L. Morel, Lisa M. Butler, Margaret M. Centenera, and Pamela J. Sykes Linh N.K. TranLinh N.K. Tran More articles by this author , Ganessan KichenadasseGanessan Kichenadasse More articles by this author , Rebecca J. OrmsbyRebecca J. Ormsby More articles by this author , Katherine L. MorelKatherine L. Morel More articles by this author , Lisa M. ButlerLisa M. Butler More articles by this author , Margaret M. CenteneraMargaret M. Centenera More articles by this author , and Pamela J. SykesPamela J. Sykes More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2576AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The anti-diabetic drug metformin (MET) and the anti-epileptic drug sodium valproate (VPA), when used alone, have shown anti-cancer effects in prostate cancer (PCa). However high doses are required which results in unacceptable toxicity. Here, we aimed to determine if the combination of MET and VPA (MET+VPA) at clinically relevant doses would (1) induce a synergistic anti-tumor effect in human PCa cell lines and patient-derived PCa explants, (2) cause minimal toxicity to normal tissues in vivo, (3) identify prognostic molecular markers for MET+VPA responses and (4) lead to rapid clinical application. METHODS Human PCa cell lines (PC-3 and LNCaP) and radical prostatectomy explants from 8 patients were analyzed for response to MET+VPA. Ki67, cleaved caspase-3, the androgen receptor (AR), and p53 expression in explants were analyzed using immunohistochemistry. The combinatorial effects of MET+VPA were calculated using the Drug Combination Index (CI). The role of p53 and AR in response to MET+VPA was determined using TP53 gene knock-down in LNCaP and TP53 ectopic expression in PC3, and AR was chemically inhibited using Enzalutamide in LNCaP. The toxicity of MET+VPA was determined using histological scoring systems for kidney and liver toxicity in nude mice. RESULTS MET+VPA synergistically inhibited proliferation in both PC-3 and LNCaP and synergistically induced apoptosis in LNCaP cells (CI<0.9). All PCa explants (pathological stage pT2C-pT3A and Gleason score 7-9) demonstrated a significant reduction (90%, p<0.001) in proliferation and a significant dose-dependent increase in apoptosis (300%, p<0.001) compared to vehicle. The p53 protein plays a role in MET+VPA as depletion of TP53 in LNCaP significantly reduced the apoptotic response by 58% (p=0.001) and the ectopic expression of TP53 in PC3 significantly increased the apoptotic response by 15% (p=0.047). The AR signaling pathway was also confirmed to play an important role in the apoptotic response to MET+VPA as Enzalutamide significantly reduced apoptosis by 28.5% (p=0.029) in LNCaP cells. No kidney or liver toxicity was detected in nude mice after 8 weeks administration of MET+VPA. These results support evaluation in a Phase I clinical trial which will start early in 2017 (Trial ID: ACTRN12616001021460p). CONCLUSIONS Our study has only taken 2 years from the first experiment to a phase I clinical trial. Although MET+VPA with an AR inhibitor may not show benefit, MET+VPA has potential to control clinically localized or metastatic PCa, particularly in tumors with functional p53 and/or AR signaling. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1108-e1109 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Linh N.K. Tran More articles by this author Ganessan Kichenadasse More articles by this author Rebecca J. Ormsby More articles by this author Katherine L. Morel More articles by this author Lisa M. Butler More articles by this author Margaret M. Centenera More articles by this author Pamela J. Sykes More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...