NVP-BEZ235, dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, prominently enhances radiosensitivity of prostate cancer cell line PC-3

Wenjie Zhu, Weijiang Fu, Likuan Hu
Cancer Biotherapy & Radiopharmaceuticals 2013, 28 (9): 665-73

BACKGROUND: Aberrant activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway may account for development of radioadaptation and is not rare in prostate cancer. Neither PI3K nor mTOR blockade could completely inhibit the pathway owing to paradoxical feedback, so we anticipate dual PI3K/mTOR blockade by NVP-BEZ235 to radiosensitize prostate cancer cells.

METHODS: We investigated into the radiosensitizing effect of NVP-BEZ235 on PC-3 cells, which are devoid of androgen receptors. Clonogenic survival and MTT assays were performed, and to pursue underlying cellular changes flow cytometric analysis of cell cycle and apoptosis as well as western blot were carried out.

RESULTS: Exposure to NVP-BEZ235 and irradiation caused a greater degree of survival inhibition than ionizing radiation (IR) or BEZ235 alone. Dual PI3K/mTOR blockade along with IR induced a G2/M arrest and enhanced proapoptotic effect. NVP-BEZ235 radiosensitized PC-3 cells through counteracting constitutive as well as IR-triggered activation of Akt/mTOR signaling.

CONCLUSIONS: Our study demonstrated that the dual PI3K/mTOR inhibitor NVP-BEZ235 prominently improved the radiosensitivity of PC-3 cells. It sensitized tumor cells to irradiation via interruption of cell cycle progression and augmentation of cell apoptosis, which was due to its constraint on constitutive and IR-elicited PI3K/Akt/mTOR signaling activation.

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