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Methylated Metabolites of Arsenic Trioxide Are More Potent Than Arsenic Trioxide as Apoptotic but not Differentiation Inducers in Leukemia and Lymphoma Cells¹

Department of Pathophysiology [G-Q. C.] and Shanghai Institute of Hematology [Z. C.], Shanghai Second Medical University, Shanghai, China; Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029 [L. Z., Y. J., R. W., S. W.]; and Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina [M. S., F. W.]

Treatment with arsenic trioxide (As₂O₃) by inducing apoptosis and partial differentiation of acute promyelocytic leukemia (APL) cells results in clinical remission in APL patients resistant to chemotherapy and all-trans-retinoic acid. As₂O₃ (iAs^III) is methylated in the liver to mono- and dimethylated metabolites, including methylarsonic acid, methylarsonous acid, dimethylarsinic acid, and dimethylarsinous acid. Methylated trivalent metabolites that are potent cytotoxins, genotoxins, and enzyme inhibitors may contribute to the in vivo therapeutic effect of iAs^III. Therefore, we compared the potency of iAs^III and trivalent metabolites using chemical precursors of methylarsonous acid and dimethylarsinous acid to induce differentiation, growth inhibition, and apoptosis. Methylarsine oxide (MAs^IIIO) and to a lesser extent iododimethylarsine were more potent growth inhibitors and apoptotic inducers than iAs^III in NB4 cells, an APL cell line. This was also observed in K562 human leukemia, lymphoma cell lines, and in primary culture of chronic lymphocytic leukemia cells, but not human bone marrow progenitor cells. Apoptosis was associated with greater hydrogen peroxide accumulation and inhibition of glutathione peroxidase activity. MAs^IIIO, in contrast to iAs^III, did not induce PML-retinoic acid receptor degradation, or restore PML nuclear bodies or differentiation in NB4 cells. In a cocultivation experiment, hepatoma-derived HepG2 cells, but not NB4 cells, methylate radiolabeled iAs^III. Methylated metabolites released from HepG2 cells are preferentially accumulated by NB4 cells. This experimental model suggests that in vivo hepatic methylation of iAs^III may contribute to As₂O₃-induced apoptosis but not differentiation of APL cells. MAs^IIIO as an apoptotic inducer should be considered in the treatment of other hematologic malignancies like lymphoma.

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