NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas

Abstract

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.

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…NVP-BEZ235 is a pan-PI3K inhibitor that acts against all of the isoforms of PI3K and PI3K mutants. Previous studies have demonstrated the efficacy of NVP-BEZ235 as an antitumor agent in vitro and in vivo in glioblastoma, multiple myeloma, melanoma, lymphoma, www.nature.com/aps Pal I et al Acta Pharmacologica Sinica npg sarcoma, breast, lung, and ovarian cancer models [84][85][86][87][88][89][90][91][92][93] . In the case of colon cancer, NVP-BEZ23 decreases cellular proliferation and causes sustained inhibition of mTORC1 and mTORC2 with a transient PI3K blockade with no subsequent effect on apoptosis either in vitro or in vivo in a GEM model.…”

PI3K–mTOR Pathway Inhibition Exhibits Efficacy Against High-grade Glioma in Clinically Relevant Mouse Models

“…All these inhibitors are under investigation for treatment of glioblastoma (18)(19)(20). We have used the orthotopic U87 brain tumor model to evaluate the antitumor efficacy of the inhibitors and further investigated ZSTK474, being the PI3K inhibitor with the most favorable brain penetration, in a more clinically relevant transgenic glioblastoma model (21).…”

NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, enhances the radiosensitivity of human glioma stem cells in vitro

“…NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, showed a dramatic effect on gliomas in various laboratory-based testing approaches. NVP-BEZ235 antagonizes the PI3K/mTOR signaling pathway and induces cell-cycle arrest, autophagy, and downregulation of vascular endothelial growth factor in glioma cells [17] . NVP-BEZ235 is also an effective radiosensitizer that inhibits ataxia telangiectasia mutated ( ATM ) and DNA-PK catalytic subunits ( DNAPKcs ), arrests cell cycle, and induces apoptosis [18][19][20] .…”