NVP-BEZ235, a dual PI3K/mTOR inhibitor synergistically potentiates the antitumor effects of cisplatin in bladder cancer cells

• Published in: International journal of oncology Vol. 45; no. 3; pp. 1027 - 1035
• Main Authors: MOON, DU G, LEE, SANG E, OH, MI M, LEE, SANG C, JEONG, SEONG J, HONG, SUNG K, YOON, CHEOL Y, BYUN, SEOK S, PARK, HONG S, CHEON, JUN
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.09.2014; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Analysis; Antineoplastic Agents - pharmacology; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bladder cancer; Cancer cells; Cancer therapies; carcinoma; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Dose-Response Relationship, Drug; Drug dosages; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Drug therapy; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; Humans; Imidazoles - pharmacology; Kinases; NVP- BEZ235; Phosphorylation; Physiological aspects; Protein kinases; Proteins; Quinolines - pharmacology; resistance; Signal Transduction - drug effects; Software; Studies; Tumors; urinary bladder; Urinary Bladder Neoplasms - drug therapy; South Korea; United States > US
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2014.2505

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.