title: Dual PI3K/mTOR inhibitor NVP-BEZ235 sensitizes docetaxel in castration resistant prostate cancer.
abstract: OBJECTIVE
  Effective therapeutic strategies that can achieve long-term improvement in patients with castration resistant prostate cancer are urgently needed. We recently reported that the activated PI3K/Akt/mTOR signaling pathway induced by docetaxel explains resistance to docetaxel in castration resistant prostate cancer. In this study we explored the efficacy of NVP-BEZ235, a dual PI3K and mTORC1/2 inhibitor, for docetaxel resistant castration resistant prostate cancer.
  
  
  METHODS
  We used the 2 human castration resistant prostate cancer cell lines C4-2 and C4-2AT6. At our laboratory C4-2AT6 cells were established from C4-2 under androgen ablated treatment for 6 months. We investigated the efficacy of NVP-BEZ235 monotherapy and NVP-BEZ235 combined with docetaxel in vitro and in vivo.
  
  
  RESULTS
  Increased phosphorylated Akt in C4-2AT6 cells was significantly inhibited by NVP-BEZ235 in a dose and time dependent manner. WST cell proliferation assay results in C4-2AT6 cells revealed that combined administration of NVP-BEZ235 and docetaxel had significant, synergistically greater cytotoxicity than NVP-BEZ235 or docetaxel monotherapy. Combined NVP-BEZ235 (40 mg/kg) and docetaxel (4 mg/kg) in vivo in a castrated mouse xenograft model inhibited C4-2AT6 tumor growth to a greater degree than in the monotherapy groups. Also, NVP-BEZ235 showed significant efficacy with docetaxel at a low concentration in vivo, suggesting that NVP-BEZ235 effectively decreased resistance to docetaxel.
  
  
  CONCLUSIONS
  Results suggest that inhibition of the PI3K/Akt/mTOR signaling pathway by NVP-BEZ235 can overcome docetaxel resistance in human castration resistant prostate cancer. Our findings provide a molecular basis for the clinical use of combined administration of NVP-BEZ235 and docetaxel in patients with castration resistant prostate cancer.
authors: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors: Yota
authors: Y
authors: Yasumizu
authors: Department of Urology, Keio University School of Medicine, Tokyo, Japan. Electronic address: akiram@a8.keio.jp.
authors: Akira
authors: A
authors: Miyajima
authors: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors: Takeo
authors: T
authors: Kosaka
authors: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors: Yasumasa
authors: Y
authors: Miyazaki
authors: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors: Eiji
authors: E
authors: Kikuchi
authors: Department of Urology, Keio University School of Medicine, Tokyo, Japan.
authors: Mototsugu
authors: M
authors: Oya
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000077143:Docetaxel; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009919:Orchiectomy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000601:surgery; D011804:Quinolines / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D043823:Taxoids / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D043823:Taxoids; D000077143:Docetaxel; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib
keywords: CRPC; MAPK; PBS; PI3K; S6; S6 ribosomal protein; castration resistant prostate cancer; dactolisib; docetaxel; drug resistance; mTOR; mTOR complex; mTORC; mammalian target of rapamycin; mitogen-activated protein kinase; p; phosphate buffered saline; phosphatidylinositol 3-kinase; phosphorylated; prostate; prostatic neoplasms