Stage-specific effect of inhibition of autophagy on chemotherapy-induced cytotoxicity.

Anticancer therapies can induce autophagy in tumor cells and the role of autophagy in these cells may depend on the type of tumor, the stage of tumorigenesis, and the nature and extent of the insult. Appropriate modification of autophagy, that is, suppression of cell-protective autophagy or enhancement of cell-killing autophagy could augment cytotoxicity caused by anticancer therapy. Imatinib mesylate is an inhibitor of tyrosine kinases and is used for the therapy of patients with tumors including leukemias, but is not effective as a monotherapy for malignant glioma. To seek a strategy to augment the therapeutic efficacy of imatinib, we examined the mode of cytotoxicity of imatinib in human malignant glioma cells. Since imatinib induced cytotoxicity associated with autophagy, we tested the effect of inhibition of autophagy on imatinib-induced cytotoxicity. We found that imatinib-induced cytotoxicity is attenuated by inhibition of autophagy at an early stage but augmented by inhibition of autophagy at a late stage through increasing apoptosis following mitochondrial damage. Though the mechanism of the stage-specific effect of inhibiting autophagy on cytotoxicity remains to be elucidated, our findings could be useful for developing a new strategy to enhance the efficacy of anticancer therapy by modulating autophagy.