Radiosensitization of prostate cancer cells by the dual PI3K/mTOR inhibitor BEZ235 under normoxic and hypoxic conditions

• Published in: Radiotherapy and oncology 2013, Vol.106 (1), p.138-146
• Main Authors: Potiron, Vincent A, Abderrhamani, Rym, Giang, Eric, Chiavassa, Sophie, Di Tomaso, Emmanuelle, Maira, Sauveur-Michel, Paris, François, Supiot, Stéphane
• Format: Article
• Language: English
• Subjects: Animals; Cell Cycle Checkpoints; Cell Hypoxia; Cell Line, Tumor; DNA Breaks; Hematology, Oncology and Palliative Medicine; Humans; Hypoxia; Imidazoles - pharmacology; Ionizing radiation; Male; Mice; mTOR; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; PI3K; Prostate cancer; Prostatic Neoplasms - pathology; Prostatic Neoplasms - radiotherapy; Quinolines - pharmacology; Radiation-Sensitizing Agents - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors
• ISSN: 0167-8140; 1879-0887
• DOI: 10.1016/j.radonc.2012.11.014

Abstract Background and purpose 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. Materials and 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% O2 ) and hypoxic (0.5% O2 ) 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.