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Originally published In Press as doi:10.1074/jbc.M100728200 on March 7, 2001

J. Biol. Chem., Vol. 276, Issue 21, 17914-17919, May 25, 2001
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Inhibition of the G2 DNA Damage Checkpoint and of Protein Kinases Chk1 and Chk2 by the Marine Sponge Alkaloid Debromohymenialdisine*

Darko CurmanDagger , Bruno Cinel§, David E. Williams§, Natalie RundleDagger , Wesley D. Block, Aaron A. Goodarzi, James R. Hutchins||, Paul R. Clarke||, Bin-Bing Zhou**, Susan P. Lees-Miller, Raymond J. Andersen§, and Michel RobergeDagger Dagger Dagger

From the Dagger  Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3, the § Departments of Chemistry and Oceanography-Earth and Ocean Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada, || Biomedical Research Centre, University of Dundee, Dundee, DD1 9SY, United Kingdom, the ** Department of Oncology Research, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, and the  Department of Biological Sciences, University of Calgary, Calgary, Alberta T2N 1N4, Canada

Cells can respond to DNA damage by activating checkpoints that delay cell cycle progression and allow time for DNA repair. Chemical inhibitors of the G2 phase DNA damage checkpoint may be used as tools to understand better how the checkpoint is regulated and may be used to sensitize cancer cells to DNA-damaging therapies. However, few inhibitors are known. We used a cell-based assay to screen natural extracts for G2 checkpoint inhibitors and identified debromohymenialdisine (DBH) from a marine sponge. DBH is distinct structurally from previously known G2 checkpoint inhibitors. It inhibited the G2 checkpoint with an IC50 of 8 µM and showed moderate cytotoxicity (IC50 = 25 µM) toward MCF-7 cells. DBH inhibited the checkpoint kinases Chk1 (IC50 = 3 µM) and Chk2 (IC50 = 3.5 µM) but not ataxia-telangiectasia mutated (ATM), ATM-Rad3-related protein, or DNA-dependent protein kinase in vitro, indicating that it blocks two major branches of the checkpoint pathway downstream of ATM. It did not cause the activation or inhibition of different signal transduction proteins, as determined by mobility shift analysis in Western blots, suggesting that it inhibits a narrow range of protein kinases in vivo.

* This work was supported by the Canadian Breast Cancer Research Initiative (to M. R.) and the National Cancer Institute of Canada (to R. J. A. and S. P. L.-M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger To whom correspondence should be addressed: 2146 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Tel.: 604-822-2304; Fax: 604-822-5227; E-mail: michel@otter.biochem.ubc.ca.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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