599 EMETINE DIHYDROCHLORIDE: A NOVEL THERAPY FOR BLADDER UROTHELIAL CARCINOMA

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research (I)1 Apr 2013599 EMETINE DIHYDROCHLORIDE: A NOVEL THERAPY FOR BLADDER UROTHELIAL CARCINOMA Kimberly Foreman, John Jesse, and Gopal Gupta Kimberly ForemanKimberly Foreman Maywood, IL More articles by this author , John JesseJohn Jesse Maywood, IL More articles by this author , and Gopal GuptaGopal Gupta Maywood, IL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1995AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES There are currently several cisplatin-based combination therapies for metastatic bladder cancer. These regimens demonstrate a 5-year survival of about 4-20%, underscoring the urgent need to develop novel therapies for these patients. Emetine, a natural product alkaloid, demonstrated anti-cancer efficacy in clinical trials in the early 1970's, but was not pursued in favor of other agents. Recently, studies showed emetine induces caspase-dependent apoptosis in leukemia cells, which was markedly enhanced when combined with cisplatin. We sought to determine the anti-cancer effects of emetine as a single agent and combined with cisplatin on human bladder cancer cell lines. METHODS Muscle invasive human bladder cancer cell lines (UMUC3, HT1376) or normal human urothelial cells were treated for 48 hours with emetine, cisplatin, or both. Cell proliferation was measured with the MTT assay. Synergy was evaluated using constant drug ratios, and the combination index (CI) calculated using Calcusyn software. Cell cycle analysis and caspase activation were evaluated by flow cytometry. RESULTS Emetine and cisplatin each inhibited bladder cancer cell proliferation, while normal urothelial cells were more resistant. Bladder cancer cells had an average IC50 of 19 nM and 4 μM for emetine and cisplatin, respectively, while normal cells had an average IC50 of 127 nM and 36 μM, respectively. When combined, emetine and cisplatin acted synergistically to inhibit bladder cancer cell proliferation with CI values reflecting moderate to strong synergy. Normal urothelial cells were relatively uneffected under the same conditions. Interestingly, emetine alone induced growth arrest, but not apoptosis in bladder cancer cells. However, when combined, emetine enhanced cisplatin-induced apoptosis. Both caspase-3 and -8 were activated in the treated cells. CONCLUSIONS Ours is the first study to evaluated emetine with or without cisplatin as a potential therapy for muscle invasive bladder cancer. We showed emetine has in vitro anti-tumor activity against two bladder cancer cell lines at nanomolar concentrations, but had little effect on normal urothelial cells. Moreover, emetine and cisplatin worked synergistically to inhibit tumor cell proliferation. When combined, emetine and cisplatin increased apoptosis compared to either drug alone, and changes in the DNA/PI profile suggest growth arrest is also involved. Our results suggest a combined therapy of emetine and cisplatin may benefit bladder cancer patients. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e245 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kimberly Foreman Maywood, IL More articles by this author John Jesse Maywood, IL More articles by this author Gopal Gupta Maywood, IL More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...