NVP-BEZ235, a novel dual PI3K–mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells

Jul 19, 2015Cancer letters

NVP-BEZ235, a new drug blocking cell growth pathways, slows human brain tumor cells and lowers resistance to chemotherapy

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Abstract

Combination treatment with temozolomide and NVP-BEZ235 significantly reduced tumor growth rates and prolonged median survival in mice.

Glioblastoma multiforme is the most common and aggressive brain tumor in adults, with many cases resistant to temozolomide.
Endogenous AKT activity may increase glioma cell resistance to temozolomide, correlating with enhanced tumor growth and invasiveness.
NVP-BEZ235 treatment induced G1 cell cycle arrest and apoptosis in glioma cell lines.
Combining temozolomide with NVP-BEZ235 resulted in synergistic inhibition of glioma cell growth and increased apoptosis markers.
NVP-BEZ235 reversed the increases in p-AKT levels associated with temozolomide treatment.
Inhibition of mTOR signaling with the combination treatment surpassed the effects of each drug used alone.

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Glioblastoma multiforme (GBM) is the most frequent and most aggressive brain tumor in adults. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. However, a considerable number of GBM cases are refractory to TMZ, the need for more effective therapeutic options is overwhelming. Mounting evidence shows that endogenous AKT (protein kinase B) activity can be activated in response to clinically relevant concentrations of TMZ. AKT activation correlated with the increased tumorigenicity, invasiveness and stemness and overexpression of an active form of AKT increases glioma cell resistance to TMZ. Previous studies also show that TMZ contributes to glioma cell apoptosis by inhibiting mTOR signaling. Thus, we hypothesized that the dual PI3K-mTOR inhibitor NVP-BEZ235 may act as antitumor agent against gliomas and potentiate the cytotoxicity of TMZ. In the present study, we found that NVP-BEZ235 treatment of glioma cell lines led to G1 cell cycle arrest, and induced apoptosis. Combination treatment with both TMZ and NVP-BEZ235 resulted in synergistically inhibited glioma cell growth and induced apoptosis (combination index CI<1) in a subset of glioma cell lines, as shown in the increased levels of Bax, and active Caspase-3, and decreased level of Bcl-2. Furthermore, NVP-BEZ235 treatment reversed p-AKT levels enhanced by TMZ. Inhibition of mTOR (p70S6K) signaling with the combination of TMZ and NVP-BEZ235 can be augmented beyond that achieved using each agent individually. In vivo xenograft models in mice, the combinatorial treatment with TMZ and NVP-BEZ235 significantly reduced tumor growth rates and prolonged median survival of tumor-bearing mice. These findings exhibit that TMZ in combination with NVP-BEZ235 act synergistically to inhibit proliferation of glioma cells by down-regulating of the PI3K-AKT-mTOR pathway, suggesting TMZ and NVP-BEZ235 combination therapy may be an option for GBM treatment.

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NVP-BEZ235, a novel dual PI3K–mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells

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