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Vol. 295, Issue 2, 724-733, November 2000

Sensitivity of Myelomonocytic Leukemia Cells to Arsenite-Induced Cell Cycle Disruption, Apoptosis, and Enhanced Differentiation Is Dependent on the Inter-Relationship between Arsenic Concentration, Duration of Treatment, and Cell Cycle Phase1

Michael J. McCabe, Jr.2 , Kameshwar P. Singh, Srikar A. Reddy, Bhadrani Chelladurai, Joel G. Pounds3 , John J. Reiners, Jr. and J. Christopher States4

Institute of Chemical Toxicology (M.J.M., K.P.S., S.A.R., B.C., J.G.P., J.J.R., J.C.S.) and Department of Pharmaceutical Sciences (M.J.M., J.G.P., J.C.S.), Wayne State University, Detroit, Michigan

Arsenite treatment has been found to induce clinical remission in patients with acute promyelocytic leukemia. Although the potential therapeutic value of arsenite may lie in triggering apoptosis, it has not been established that cytotoxicity is the sole mechanism of action. We have used a myelomonocytic leukemia cell line (U937) to characterize the concentration-dependent effects of arsenite on cell growth, viability, apoptosis, and differentiation. Arsenite has multiple effects on U937 cells. Low concentrations of arsenite (i.e., <= 1 µM) potentiate vitamin-D3-induced differentiation. Two markers of monocyte differentiation, Mac-1 expression and nitroblue tetrazolium reduction, are increased in arsenite-exposed, D3-costimulated cells. Concentrations of arsenite >10 µM rapidly induce the death of cells irrespective of cell cycle phase. Intermediate concentrations of arsenite (i.e., 5 to 10 µM) are cytostatic initially. Cell cycle analysis using elutriated, synchronous cell populations revealed that intermediate concentrations of arsenite delay both G1 and G2 transit. G2 cells appear to be most sensitive to arsenite, in that transit through G2/M is more delayed than transit through G1, and apoptosis is induced in these cells as they emerge from an aberrant G2/M. Arsenite-induced apoptosis was caspase-3 dependent. Arsenite-mediated cytotoxicity was reduced in the presence of the broad caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone; however, caspase inhibition did not reverse arsenite-induced cytostasis. Thus, arsenite has multiple effects on U937 cells that are dependent on concentration and cell cycle phase. Specifically, cell cycle transit and differentiation are more sensitive to arsenite than is the induction of apoptosis.

1 This work was supported in part by a pilot project awarded through the National Institutes of Health Environmental Health Sciences Center Grant P30 ES06639 and by an Interdisciplinary Research Seed Fund awarded through the Office of Research and Sponsored Programs at Wayne State University. S.A.R. was supported, in part, by the high school student apprenticeship Grant R25 RR12242. K.P.S. was supported, in part, by R01 ES09392.

2 Present address: Michael J. McCabe, Jr., Department of Environmental Medicine, University of Rochester School of Medicine, 575 Elmwood Ave., Box EHSC, Rochester, NY 14642.

3 Present address: Joel G. Pounds, Molecular Biosciences Department, Pacific Northwest National Laboratory, P.O. Box 999, Mail Stop P7-58, Richland, WA 99352.

4 Present address: J. Christopher States, Department of Pharmacology & Toxicology, University of Louisville School of Medicine, 570 S. Preston St., Suite 221 Louisville, KY 40292.

0022-3565/00/2952-0724$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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