Induction of autophagic cell death in malignant glioma cells by arsenic trioxide.
Recent clinical data shows that arsenic trioxide (As(2)O(3)) causes remission in patients with acute promyelocytic leukemia and multiple myeloma without severe side effects. Laboratory data suggest that As(2)O(3) induces apoptosis or cell differentiation of hematopoietic or solid tumor cells. To date, there has been no study on the effects of As(2)O(3) on glioma cells. In this study, we investigated the in vitro effect of As(2)O(3) on cell growth inhibition and cell death mechanisms in human glioma cells. As(2)O(3) 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 IC(50) of As(2)O(3) for all of the tumor cell lines was <2 micro M. Previous studies have shown that this is a clinically safe concentration. Treatment with 2 micro M As(2)O(3) induced G(2)/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 micro M As(2)O(3). Caspase inhibitors did not halt As(2)O(3)-induced cell death. Furthermore, combination of As(2)O(3) with bafilomycin A1 autophagy inhibitor enhanced the antitumor effect of As(2)O(3) through induction of apoptosis. These findings suggest that As(2)O(3) at a clinically safe concentration may be an effective chemotherapeutic agent for malignant gliomas.
Department of Neurosurgery, Mount Sinai School of Medicine, New York, New York 10029, USA.
Takao
T
Kanzawa
Yasuko
Y
Kondo
Hideaki
H
Ito
Seiji
S
Kondo
Isabelle
I
Germano
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D018942:Macrolides; D008938:Mitosis / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000590:Amino Acid Chloromethyl Ketones; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001152:Arsenicals; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D018942:Macrolides; D010087:Oxides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C040929:bafilomycin A1; D000077237:Arsenic Trioxide