NVP-BEZ235, A Novel Dual PI3K/mTOR Inhibitor, Elicits Multifaceted Antitumor Activities in Human Gliomas

Aberrant genetic alternations in human gliomas such as amplification of EGFR , mutation and/or deletion of tumor suppressor gene PTEN , and mutations of PIK3CA contribute to constitutive activation of the PI3K pathway. We investigated the potential anti-tumor activity of NVP-BEZ235, which is a novel dual PI3K/mTOR inhibitor, in gliomas. The compound suppressed glioma cell proliferation with IC 50 values in the low nM range by specifically inhibiting the activity of target proteins, including Akt, S6K1, S6, and 4EBP1 in the PI3K/Akt/mTOR signaling pathway. NVP-BEZ235 treatment of glioma cell lines led to G 1 cell cycle arrest, and induced autophagy. Furthermore, expression of the vascular endothelial growth factor (VEGF), which is an important angiogenic modulator in glioma cells, was significantly decreased, suggesting that NVP-BEZ235 may also exert an anti-angiogenic effect. Preclinical testing of the therapeutic efficacy of NVP-BEZ235 demonstrated that it significantly prolonged the survival of tumor bearing animals without causing any obvious toxicity. Tumor extracts harvested from animals post-treatment showed that the compound inhibited the activity of target proteins in the PI3K/Akt/mTOR cascade. Immunohistochemical analyses also showed a significant reduction in staining for VEGF von Willebrand factor (factor VIII) in NVP-BEZ235-treated tumor sections as compared with controls, further confirming that NVP-BEZ235 has an anti-angiogenic effect in vivo . We conclude from these findings that NVP-BEZ235 antagonizes PI3K and mTOR signaling, and induces cell cycle arrest, down-regulation of VEGF, and autophagy. These results warrant further development of NVP-BEZ235 for clinical trials for human gliomas or other advanced cancers with altered PI3K/Akt/mTOR signaling.