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

Int J Oncol. 2015 Jul;47(1):377-83. doi: 10.3892/ijo.2015.2995. Epub 2015 May 11.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravesical
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imidazoles / administration & dosage*
  • Imidazoles / pharmacology
  • Mice
  • Neoplasm Transplantation
  • Phosphoinositide-3 Kinase Inhibitors*
  • Quinolines / administration & dosage*
  • Quinolines / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinolines
  • TOR Serine-Threonine Kinases
  • dactolisib