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

Masashi Matsushima, Eiji Kikuchi, Kazuhiro Matsumoto, Seiya Hattori, Toshikazu Takeda, Takeo Kosaka, Akira Miyajima, Mototsugu Oya

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

NVP-BEZ235 is an inhibitor of both phosphati-dylinositol 3-kinase (PI3K) and mammalian target of rapamycin complex 1/2 (mTORCl/2), and its antitumor activity is expected to be higher than that of mTORCl 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 p4EBPl 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/1) 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 p4EBPl 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 p4EBPl 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.

Original languageEnglish
Pages (from-to)377-383
Number of pages7
JournalInternational journal of oncology
Volume47
Issue number1
DOIs
Publication statusPublished - 2015 Jul 1

Keywords

  • Bladder cancer
  • Intravesical therapy
  • MTOR
  • NVP-BEZ235
  • Novel antitumor agents

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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