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Induction of Autophagic Cell Death in Malignant Glioma Cells by Arsenic Trioxide

Department of Neurosurgery, Mount Sinai School of Medicine, New York, New York 10029

Recent clinical data shows that arsenic trioxide (As₂O₃) causes remission in patients with acute promyelocytic leukemia and multiple myeloma without severe side effects. Laboratory data suggest that As₂O₃ induces apoptosis or cell differentiation of hematopoietic or solid tumor cells. To date, there has been no study on the effects of As₂O₃ on glioma cells. In this study, we investigated the in vitro effect of As₂O₃ on cell growth inhibition and cell death mechanisms in human glioma cells. As₂O₃ significantly inhibited the proliferation of all six of the glioma cell lines (U373, U87, U251, GB1, A-172, and T98G) tested in this study in a dose-dependent manner. The IC₅₀ of As₂O₃ for all of the tumor cell lines was <2 µM. Previous studies have shown that this is a clinically safe concentration. Treatment with 2 µM As₂O₃ induced G₂/M arrest in all of the glioma cell lines. Autophagy (programmed cell death type II), but not apoptosis (programmed cell death type I), was detected by electron microscopy in U-373-MG cells treated with 2 µM As₂O₃. Caspase inhibitors did not halt As₂O₃-induced cell death. Furthermore, combination of As₂O₃ with bafilomycin A1 autophagy inhibitor enhanced the antitumor effect of As₂O₃ through induction of apoptosis. These findings suggest that As₂O₃ at a clinically safe concentration may be an effective chemotherapeutic agent for malignant gliomas.

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