LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway

The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. However, a considerable number of glioblastoma (GBM) cases are refractory to TMZ. Previous studies have revealed that the PI3K/Akt pathway is activated in an ataxia telangiectasia and Rad3 related-dependent manner in response to TMZ. Thus, we hypothesized that PI3K inhibitors may act as antitumor agents against gliomas and potentiate the cytotoxicity of TMZ. The cytotoxicity of a PI3K inhibitor, LY294002, was examined both alone and in combination with TMZ in human glioma cell lines. Proliferation of tumor cells treated with LY294002 in combination with TMZ was significantly suppressed compared to treatment with either drug used alone. The combination treatment induced a higher apoptosis rate, while reducing the invasive capability of U87 cells. The apoptosis-associated proteins, cleaved-caspase-3 and Bax, were more significantly up-regulated by the combined treatment than by TMZ used alone. In addition, p-Akt and Bcl-2, which can promote TMZ resistance, were markedly decreased by LY294002. These findings suggest that LY294002 enhances the cytotoxicity of TMZ by down-regulation of the PI3K/Akt pathway.