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Arsenic trioxide, an acute promyelocytic leukemia chemotherapeutic, may be an efficacious treatment for other cancers. Understanding the mechanism as well as genetic and molecular characteristics associated with sensitivity to arsenite-induced cell death is key to providing effective chemotherapeutic usage of arsenite. Arsenite sensitivity correlates with deficient p53 pathways in multiple cell lines. The role of p53 in preventing arsenite-induced mitotic arrest-associated apoptosis (MAAA), a form of mitotic catastrophe, was examined in TR9-7 cells, a model cell line with p53 exogenously regulated in a tetracycline-off expression system. Arsenite activated G 1 and G 2 cell cycle checkpoints independently of p53, but mitotic catastrophe occurred preferentially in p53 inhibit cyclin B/CDC2 by CDC2 tyrosine-15 phosphorylation and direct binding, respectively. CDC2-Y15-P was transiently elevated in arsenite-treated p53 (ϩ) cells but persisted in p53 (Ϫ) cells. Arsenite induced p53-S15-P and p21 CIP1/WAF1 only in p53 (ϩ) cells. P21 CIP1/WAF1 -siRNA-treated p53 (ϩ) cells were similar to p53(Ϫ) cells in mitotic index and cell cycle protein levels. p53-inducible proteins GADD45␣ and 14-3-3 are capable of inhibiting cyclin B/CDC2 but did not play a p53-dependent role in mitotic escape in TR9-7 cells. The data indicate that p53 mediates cyclin B/CDC2 inactivation and mitotic release directly via p21 CIP1/WAF1 induction.

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. G 2 /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.