Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, PR China.
Mol Med Rep. 2012 Feb;5(2):575-9. doi: 10.3892/mmr.2011.674. Epub 2011 Nov 11.
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.
替莫唑胺（TMZ）的引入提高了恶性神经胶质瘤的化疗水平。然而，相当数量的胶质母细胞瘤（GBM）对 TMZ 具有抗药性。先前的研究表明，PI3K/Akt 通路在 ATM 和 Rad3 相关蛋白依赖性方式下被激活，以响应 TMZ。因此，我们假设 PI3K 抑制剂可能作为抗肿瘤剂对抗神经胶质瘤，并增强 TMZ 的细胞毒性。PI3K 抑制剂 LY294002 的细胞毒性单独或与 TMZ 联合用于人神经胶质瘤细胞系进行了检测。与单独使用任何一种药物相比，用 LY294002 联合 TMZ 处理的肿瘤细胞的增殖明显受到抑制。联合治疗诱导更高的细胞凋亡率，同时降低 U87 细胞的侵袭能力。与单独使用 TMZ 相比，联合治疗更显著地上调了凋亡相关蛋白 cleaved-caspase-3 和 Bax。此外，可促进 TMZ 耐药的 p-Akt 和 Bcl-2 也被 LY294002 显著下调。这些发现表明，LY294002 通过下调 PI3K/Akt 通路增强 TMZ 的细胞毒性。
