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Antitumor Drug Fostriecin Inhibits the Mitotic Entry Checkpoint and Protein Phosphatases 1 and 2A¹

Department of Biochemistry and Molecular Biology [M. R., C. T., S. M. F. H., H. A.], and Biomedical Research Centre and Department of Medicine [K. W. H., F. R. J.], University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3

In most eukaryotic cells, entry into mitosis is tightly controlled and requires completely replicated and undamaged DNA. We show that the antitumor drug, fostriecin, interferes with this control; it induces cycling cells to enter mitosis prematurely, and it can overcome the mitotic entry checkpoint, forcing into mitosis cells that were arrested in the division cycle by treatment with the DNA replication inhibitor aphidicolin or with the DNA-damaging agents camptothecin and teniposide. This effect was observed in all rodent, simian, and human cell lines tested. Fostriecin also hampers progression through the later stages of mitosis as determined by the absence of normal half-spindles, anaphase figures, and telophase figures. The only previously known target for fostriecin is topoisomerase II, which is inhibited in vitro with a 50% inhibitory concentration of 40 µM (T. J. Boritzki, T. S. Wolfard, J. A. Besserer, R. C. Jackson, and D. W. Fry. Inhibition of type II topoisomerase by fostriecin. Biochem. Pharmacol., 37: 4063–4068, 1988). We show that fostriecin is a more potent inhibitor of protein phosphatase 1, with a 50% inhibitory concentration of 4 µM and protein phosphatase 2A, with a 50% inhibitory concentration of 40 nM. Inhibition of the mitotic entry checkpoint and inhibition of protein phosphatases are novel properties for antitumor drugs with potential or proven therapeutic value.

¹ This work was supported in part by the Canadian Genetic Diseases Network (F. R. J.) and by grants from the British Columbia Health Research Foundation and the Cancer Research Society (M. R.). C. T. was supported by an Evelyn Martin Memorial Fellowship and by a studentship from the Medical Research Council of Canada. K. W. H. is a recipient of a Canadian Arthritis Society studentship. F. R. J. is a research scientist of the Canadian Arthritis Society. M. R. is a scholar of the Medical Research Council of Canada.

² These authors contributed equally to the study.

³ To whom requests for reprints should be addressed, at Department of Biochemistry and Molecular Biology, 2146 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.

⁴ Present address: Kinetek Corp., Vancouver, British Columbia, Canada.

Received 7/27/94. Accepted 10/ 3/94.

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