Aberrant genetic alternations in human
gliomas, such as amplification of
epidermal growth factor receptor, mutation and/or deletion of tumor suppressor gene PTEN, and mutations of PIK3CA, contribute to constitutive activation of the
phosphatidylinositol 3-kinase (PI3K) pathway. We investigated the potential antitumor activity of
NVP-BEZ235, which is a novel dual PI3K/
mammalian target of rapamycin (mTOR) inhibitor in
gliomas. The compound suppressed
glioma cell proliferation with IC(50) values in the low nanomolar 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 antiangiogenic effect. Preclinical testing of the therapeutic efficacy of
NVP-BEZ235 showed that it significantly prolonged the survival of
tumor-bearing animals without causing any obvious toxicity.
Tumor extracts harvested from animals
after 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 compared with controls, further confirming that
NVP-BEZ235 has an antiangiogenic 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.