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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 18, 2005; DOI: 10.1124/jpet.104.080713

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Received for publication November 12, 2004.
Revised February 16, 2005.
Accepted for publication February 17, 2005.

Arsenite delays progression through each cell cycle phase and induces apoptosis following G2/M arrest in U937 myeloid leukemia cells

Geniece McCollum 1, Peter C. Keng 2, J. Christopher States 3, Michael J. McCabe 1*

1 University of Rochester School of Medicine 2 University of Rochester 3 University of Louisville

* Address correspondence to: E-mail: michael_mccabe{at}urmc.rochester.edu

Abstract

Arsenic is a well-known toxicant and carcinogen that is also effective as a chemotherapeutic in the treatment of acute promyelocytic leukemia. Although its effects on humans are well-documented, arsenic's mechanism of action is not well-understood. Its ability to act as a carcinogen and as a chemotherapeutic seems paradoxical. However, cancer cell transformation and cancer cell destruction can both occur through perturbations of the cell cycle machinery, making cell cycle function a likely target of arsenic action. Arsenic has previously been shown to inhibit cancer cell cycle progression, but the targeted cell cycle phase has been debated. This study was designed to identify the cell cycle phase at which U937 cells are most sensitive to arsenite-induced growth inhibition. Centrifugal elutriation was used to divide asynchronous cell cultures into specific cell cycle phase-enriched fractions. These fractions were monitored for cell cycle phase progression in the presence and absence of sodium arsenite. We found an overall reduction in cell cycle progression rather than induction of arrest at one specific checkpoint. G2/M is the phase most sensitive to arsenite-induced apoptosis. However, arsenite profoundly affects U937 cell growth by increasing the length of time it takes cells to transit each phase of the cell cycle. Future study of cell cycle inhibition by arsenic should consider that the effect may not be mediated by the major cell cycle checkpoints. Arsenic's ability to inhibit growth in any cell cycle phase may increase its value as a chemotherapeutic used together with other, more phase-selective agents, such as camptothecin.


Key words: apoptosis, arsenite, caspase-3, cell cycle, centrifugal elutriation, chemotherapy


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