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

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

doi:10.3892/ijo.2014.2505

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

Authors:
- Du G. Moon
- Sang E. Lee
- Mi M. Oh
- Sang C. Lee
- Seong J. Jeong
- Sung K. Hong
- Cheol Y. Yoon
- Seok S. Byun
- Hong S. Park
- Jun Cheon
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Affiliations: Department of Urology, College of Medicine, Korea University, Guro Hospital, Seoul, Republic of Korea, Department of Urology, School of Medicine, Seoul National University, Bundang Hospital, Gyeonggi‑do, Seoul, Republic of Korea, Department of Urology, College of Medicine, Korea University, Anam Hospital, Seoul, Republic of Korea
Published online on: June 19, 2014 https://doi.org/10.3892/ijo.2014.2505
Pages: 1027-1035
Copyright: © Moon et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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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.

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