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Microtubule-interfering agents (MIAs), such as vincristine, are widely used for the treatment of cancer, and are included in many treatment regimens for childhood brain tumors. The anticancer properties of MIAs have been attributed in part to interference with microtubule assembly, impairment of mitosis, and cytoskeletal changes, with additional effects on mitogen-activated protein kinase signaling and caspase activation. Because malignant gliomas commonly have dysregulation of PI3K/Akt signaling, which can promote cell survival and potentially limit the activity of such agents, we questioned whether PI3K inhibition with LY294002 could potentiate the efficacy of vincristine in a panel of glioma cell lines versus normal astrocytes. We therefore examined the effects of the LY294002 and vincristine, alone and in combination, on cell survival, signal transduction and apoptosis in a series of malignant glioma cell lines versus normal astrocytes. Simultaneous exposure to these inhibitors significantly induced cell death, and inhibited proliferation and clonogenicity of the glioma cell lines. Quantitative analysis revealed that enhancement by LY294002 of vincristine-induced cytotoxicity was synergistic, leading to pronounced caspase activation at concentrations that had no significant effects on control cells. The enhanced cytotoxicity of this combination was associated with significant activation of p38 MAPK signaling and induction of G2/M blockade on cell cycle analysis. Pre-treatment with either SB203580 or z-VAD.fmk, selective inhibitors of p38 MAPK and caspase signaling, respectively, abrogated the apoptotic response to the combination of LY294002 and vincristine. Taken together, these findings demonstrate that PI3K/Akt inhibition can potentiate the effects of vincristine, and that the combination of molecularly targeted therapies and conventional agents could provide a potent strategy to treat patients with malignant gliomas.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]