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Research Articles: Therapeutics

Effect of combined DNA repair inhibition and G₂ checkpoint inhibition on cell cycle progression after DNA damage

¹ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada and ² Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

Requests for reprints: Michel Roberge, Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Phone: 604-822-2304; Fax: 604-822-5227. E-mail: michelr{at}interchange.ubc.ca

Abstract

In response to DNA damage, cell survival can be enhanced by activation of DNA repair mechanisms and of checkpoints that delay cell cycle progression to allow more time for DNA repair. Inhibiting both responses with drugs might cause cancer cells to undergo cell division in the presence of lethal amounts of unrepaired DNA. However, we show that interfering with DNA repair via inhibition of DNA-dependent protein kinase (DNA-PK) reduces the ability of checkpoint inhibitors to abrogate G₂ arrest and their radiosensitizing activity. Cells exposed to the DNA-PK inhibitor AMA37, DNA-PK-deficient cells, and nonhomologous end joining–deficient cells all enter prolonged G₂ arrest after exposure to ionizing radiation doses as low as 2 Gy. The checkpoint kinase Chk2 becomes rapidly and transiently overactivated, whereas Chk1 shows sustained overactivation that parallels the prolonged accumulation of cells in G₂. Therefore, in irradiated cells, DNA repair inhibition elicits abnormally strong checkpoint signaling that causes essentially irreversible G₂ arrest and strongly reduces the ability of checkpoint kinase inhibitors to overcome G₂ arrest and radiosensitize cells. Variable levels of proteins controlling DNA repair have been documented in cancer cells. Therefore, these results have relevance to the development of DNA-PK inhibitors and G₂ checkpoint inhibitors as experimental therapeutic approaches to enhance the selective killing of tumor cells by radiotherapy or DNA-damaging chemotherapeutic agents. [Mol Cancer Ther 2006;5(4):885–92]

Grant support: National Cancer Institute of Canada (M. Roberge). C.M. Sturgeon is a recipient of a National Sciences and Engineering Research Council postgraduate scholarship.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 9/ 7/05; revised 1/19/06; accepted 2/15/06.

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