MP83-04 SYNERGISTIC ANTITUMOR EFFECT OF SATRAPLATIN AND NVP-BEZ235 IN CISPLATIN-RESISTANT HUMAN BLADDER CANCER CELLS (2016)

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2016MP83-04 SYNERGISTIC ANTITUMOR EFFECT OF SATRAPLATIN AND NVP-BEZ235 IN CISPLATIN-RESISTANT HUMAN BLADDER CANCER CELLS Cheol Yong Yoon, Mi Kyung Kong, Hyun Gyu Ahn, Seung Gu Kang, Jang Hee Han, Yong Jin Kang, Won Sik Jang, Joong Shik Lee, Young Sik Kim, Hong Seok Park, In Rae Cho, Jun Cheon, and Young Deuk Choi Cheol Yong YoonCheol Yong Yoon More articles by this author , Mi Kyung KongMi Kyung Kong More articles by this author , Hyun Gyu AhnHyun Gyu Ahn More articles by this author , Seung Gu KangSeung Gu Kang More articles by this author , Jang Hee HanJang Hee Han More articles by this author , Yong Jin KangYong Jin Kang More articles by this author , Won Sik JangWon Sik Jang More articles by this author , Joong Shik LeeJoong Shik Lee More articles by this author , Young Sik KimYoung Sik Kim More articles by this author , Hong Seok ParkHong Seok Park More articles by this author , In Rae ChoIn Rae Cho More articles by this author , Jun CheonJun Cheon More articles by this author , and Young Deuk ChoiYoung Deuk Choi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2186AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In this study we explored the antitumor effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor in cisplatin-resistant human bladder cancer cells and its synergistic interaction with satraplatin, orally available 3rd generation platinum. METHODS A human bladder cancer cell lines with different sensitivity to cisplatin (T24, T24R2, 253J, UMUC14, SW1710, HTB5) were exposed to escalating doses of NVP-BEZ235 (0.5-4.0µM) alone or in combination with satraplatin (1.5-24.0µM) and antitumor effects was determined by CCK-8 assay. Based on dose-response study, synergistic interaction between NVP-BEZ235 and satraplatin was evaluated by combination index (CI), three-dimensional model, and clonogenic assay. Changes in cell cycle was analyzed by flowcytometry. Expression of apoptosis (caspase 3, 8, 9, cIAP1, cIAP2, XIAP)-, cell cycle- (cyclin A, B1, D1) and survival-related protein (PI3K, Akt) expression was assessed by western blot respectively. RESULTS The combination of NVP-BEZ235 and satraplatin caused significant synergistic antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range (35-100%) and reduced IC50 of NVP-BEZ235 and satraplatin by 2.2-fold and 2.7-fold respectively. Three-dimensional synergy analysis resulted in synergy volume 610.21μM/mL2% indicating a strong synergistic effect of combination therapy. Clonogenic assay showed results compatible with dose-response study. Flowcytometric analysis indicated that underlying mechanism in the synergistic interaction between two drugs are primarily from the induction of apoptosis and G2-phase cell cycle arrest. Western blot anaylsis also demonstrated that combination therapy causes cell cycle arrest and caspase-dependent apoptosis. NVP-BEZ235 suppressed PI3K/mTOR signaling without any paradoxical induction of Akt activity while combination with satraplatin didn't show any additional NVP-BEZ235-induced suppression of PI3K/Akt/mTOR signaling. CONCLUSIONS In conclusion, the present study demonstrated that PI3K/mTOR dual inhibitor NVP-BEZ235 can synergistically potentiate antitumor effect of satraplatin in cisplatin-resistant bladder cancer cells through the suppression of cell cycle progression and survival pathway and also induction of caspase-dependent apoptosis. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1082 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Cheol Yong Yoon More articles by this author Mi Kyung Kong More articles by this author Hyun Gyu Ahn More articles by this author Seung Gu Kang More articles by this author Jang Hee Han More articles by this author Yong Jin Kang More articles by this author Won Sik Jang More articles by this author Joong Shik Lee More articles by this author Young Sik Kim More articles by this author Hong Seok Park More articles by this author In Rae Cho More articles by this author Jun Cheon More articles by this author Young Deuk Choi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...