Intravesical dual PI3K/mTOR complex 1/2 inhibitor NVP-BEZ235 therapy in an orthotopic bladder cancer model

  • Authors:
    • Masashi Matsushima
    • Eiji Kikuchi
    • Kazuhiro Matsumoto
    • Seiya Hattori
    • Toshikazu Takeda
    • Takeo Kosaka
    • Akira Miyajima
    • Mototsugu Oya
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  • Published online on: May 11, 2015     https://doi.org/10.3892/ijo.2015.2995
  • Pages: 377-383
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Abstract

NVP-BEZ235 is an inhibitor of both phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin complex 1/2 (mTORC1/2), and its antitumor activity is expected to be higher than that of mTORC1 inhibitors because it inhibits the upregulation of pAkt through mTORC2. We examined the efficacy of intravesical NVP-BEZ235 therapy in the treatment of bladder cancer using an orthotopic bladder cancer model. The cytotoxic effects of various concentrations of NVP-BEZ235 in MBT-2 cells were examined using a WST assay. The expression of pAkt, pS6 and p4EBP1 was evaluated in MBT-2 cells treated with NVP-BEZ235 using western blotting. Orthotopic models were established by implanting MBT-2 cells into the bladders of female C3H/He mice. We assigned C3H/He mice to 2 groups: a control group treated with vehicle control (n=15), and a group intravesically administered 40 µM (18.78 mg/l) of NVP-BEZ235 (n=15). NVP-BEZ235 inhibited the viability of MBT-2 cells in a dose-dependent manner. Furthermore, the expression of pAkt, pS6, and p4EBP1 was inhibited in NVP-BEZ235-treated MBT-2 cells. Bladder weights were significantly lower in the NVP-BEZ235-treated group than in the control group (P<0.05). An analysis of the tumor tissues revealed that the NVP-BEZ235 treatment strongly reduced pAkt, pS6 and p4EBP1 levels. An immunohistochemical analysis showed that NVP-BEZ235 significantly inhibited the expression of pS6. Intravesically administered NVP-BEZ235 exerted significant antitumor effects in the orthotopic bladder cancer model by inhibiting the PI3K/Akt/mTOR pathway. The intravesical instillation of a dual PI3K/mTORC1/2 inhibitor may represent a novel therapy for the treatment of bladder cancer.
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July-2015
Volume 47 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Matsushima M, Kikuchi E, Matsumoto K, Hattori S, Takeda T, Kosaka T, Miyajima A and Oya M: Intravesical dual PI3K/mTOR complex 1/2 inhibitor NVP-BEZ235 therapy in an orthotopic bladder cancer model. Int J Oncol 47: 377-383, 2015.
APA
Matsushima, M., Kikuchi, E., Matsumoto, K., Hattori, S., Takeda, T., Kosaka, T. ... Oya, M. (2015). Intravesical dual PI3K/mTOR complex 1/2 inhibitor NVP-BEZ235 therapy in an orthotopic bladder cancer model. International Journal of Oncology, 47, 377-383. https://doi.org/10.3892/ijo.2015.2995
MLA
Matsushima, M., Kikuchi, E., Matsumoto, K., Hattori, S., Takeda, T., Kosaka, T., Miyajima, A., Oya, M."Intravesical dual PI3K/mTOR complex 1/2 inhibitor NVP-BEZ235 therapy in an orthotopic bladder cancer model". International Journal of Oncology 47.1 (2015): 377-383.
Chicago
Matsushima, M., Kikuchi, E., Matsumoto, K., Hattori, S., Takeda, T., Kosaka, T., Miyajima, A., Oya, M."Intravesical dual PI3K/mTOR complex 1/2 inhibitor NVP-BEZ235 therapy in an orthotopic bladder cancer model". International Journal of Oncology 47, no. 1 (2015): 377-383. https://doi.org/10.3892/ijo.2015.2995