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

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.

• Authors: Masashi Matsushima, Eiji Kikuchi, Kazuhiro Matsumoto, Seiya Hattori, Toshikazu Takeda, Takeo Kosaka, Akira Miyajima, Mototsugu Oya
• Journal: International journal of oncology (Int J Oncol) Vol. 47 Issue 1 Pg. 377-83 (Jul 2015) ISSN: 1791-2423 [Electronic] Greece
• PMID: 25963317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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