title: 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.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Matsushima
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kikuchi
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Hattori
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Takeda
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Kosaka
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Miyajima
authors.affiliation: Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Oya
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib