title: Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions.
abstract: OBJECTIVE
  Despite appropriate radiotherapy, high-risk prostate cancer patients often experience local relapse and progression to metastatic disease. Radioresistance may be due to tumor-hypoxia but also due to the PTEN mutation/deletion present in 70% prostate cancers. We investigated whether the novel PI3K/mTOR inhibitor BEZ235 might sensitize prostate cancer cells to radiation and reduce hypoxia-induced radioresistance.
  
  
  METHODS
  The potential radiosensitizing properties of BEZ235 were investigated in vitro and in vivo using two prostate cancer cell lines, PC3 (PTEN(-/-)) and DU145 (PTEN(+/+)), under normoxic (21% O(2)) and hypoxic (0.5% O(2)) conditions.
  
  
  RESULTS
  BEZ235 rapidly inhibited PI3K and mTOR signaling in a dose dependent manner and limited tumor cell proliferation and clonogenic survival in both cell lines independently of PTEN status. In vivo, BEZ235 pretreatment enhanced the efficacy of radiation therapy on PC3 xenograft tumors in mice without inducing intestinal radiotoxicity. In culture, BEZ235 radiosensitized both cell lines in a comparable manner. Moreover, BEZ235 inhibited PI3K/mTOR activation and radiosensitized both cell lines under normoxia and hypoxia. BEZ235 radiosensitizing effects correlated with a decrease in γH2AX foci repair and increased G2/M cell cycle arrest.
  
  
  CONCLUSIONS
  BEZ235 is a potent radiosensitizer of normoxic and hypoxic prostate cancer cells.
authors: INSERM, UMR892, Nantes, France.
authors: Vincent A
authors: VA
authors: Potiron
authors: Rym
authors: R
authors: Abderrahmani
authors: Rym
authors: R
authors: Abderrhamani
authors: Eric
authors: E
authors: Giang
authors: Sophie
authors: S
authors: Chiavassa
authors: Emmanuelle
authors: E
authors: Di Tomaso
authors: Sauveur-Michel
authors: SM
authors: Maira
authors: François
authors: F
authors: Paris
authors: Stéphane
authors: S
authors: Supiot
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D053960:DNA Breaks; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D011804:Quinolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D011838:Radiation-Sensitizing Agents; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib