title: NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells.
abstract: The PI3K/Akt/mTOR pathway is a prototypic survival pathway and constitutively activated in many malignant conditions. Moreover, activation of the PI3K/Akt/mTOR pathway confers resistance to various cancer therapies and is often associated with a poor prognosis. 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 cisplatin. A human bladder cancer cell line with cisplatin resistance was exposed to escalating doses of NVP-BEZ235 alone or in combination with cisplatin and antitumor effects was determined by the CCK-8 assay. Based on a dose-response study, synergistic interaction between NVP-BEZ235 and cisplatin was evaluated by combination index (CI), three-dimensional model and clonogenic assay. The combination of NVP-BEZ235 and cisplatin caused significant synergistic antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range and reduced the IC50 of NVP-BEZ235 and cisplatin by 5.6- and 3.6-fold, respectively. Three-dimensional synergy analysis resulted in a synergy volume of 388.25 µM/ml2% indicating a strong synergistic effect of combination therapy. The combination therapy caused cell cycle arrest and caspase-dependent apoptosis. Although NVP-BEZ235 suppressed PI3K/mTOR signaling without any paradoxical induction of Akt activity, it caused MEK/ERK pathway activation. The present study demonstrated that the PI3K/mTOR dual inhibitor NVP-BEZ235 can synergistically potentiate the antitumor effects of cisplatin in cisplatin-resistant bladder cancer cells though the suppression of cell cycle progression and the survival pathway as well as induction of caspase-dependent apoptosis.
authors: Department of Urology, College of Medicine, Korea University, Guro Hospital, Seoul, Republic of Korea.
authors: Du G
authors: du G
authors: Moon
authors: Department of Urology, School of Medicine, Seoul National University, Bundang Hospital, Gyeonggi‑do, Seoul, Republic of Korea.
authors: Sang E
authors: SE
authors: Lee
authors: Department of Urology, College of Medicine, Korea University, Guro Hospital, Seoul, Republic of Korea.
authors: Mi M
authors: MM
authors: Oh
authors: Department of Urology, School of Medicine, Seoul National University, Bundang Hospital, Gyeonggi‑do, Seoul, Republic of Korea.
authors: Sang C
authors: SC
authors: Lee
authors: Department of Urology, School of Medicine, Seoul National University, Bundang Hospital, Gyeonggi‑do, Seoul, Republic of Korea.
authors: Seong J
authors: SJ
authors: Jeong
authors: Department of Urology, School of Medicine, Seoul National University, Bundang Hospital, Gyeonggi‑do, Seoul, Republic of Korea.
authors: Sung K
authors: SK
authors: Hong
authors: Department of Urology, College of Medicine, Korea University, Guro Hospital, Seoul, Republic of Korea.
authors: Cheol Y
authors: CY
authors: Yoon
authors: Department of Urology, School of Medicine, Seoul National University, Bundang Hospital, Gyeonggi‑do, Seoul, Republic of Korea.
authors: Seok S
authors: SS
authors: Byun
authors: Department of Urology, College of Medicine, Korea University, Guro Hospital, Seoul, Republic of Korea.
authors: Hong S
authors: HS
authors: Park
authors: Department of Urology, College of Medicine, Korea University, Anam Hospital, Seoul, Republic of Korea.
authors: Jun
authors: J
authors: Cheon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D011804:Quinolines; D002945:Cisplatin; C531198:dactolisib