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Sensitization of Cancer Cells to DNA Damage-induced Cell Death by Specific Cell Cycle G₂ Checkpoint Abrogation¹

Department of Molecular Genetics, Nagoya City University School of Medicine, Nagoya 467-8601 [M. S., T. K., H. H., T. O.], and Department of Surgery, Fujita Health University School of Medicine, Toyoake 470-1101 [M. S., T. F.], Japan

We devised two short peptides corresponding to amino acids 211–221 of human Cdc25C fused with a part of HIV1-TAT. These peptides inhibited hChk1 and Chk2/HuCds1 kinase activity in vitro and specifically abrogated the G₂ checkpoint in vivo. These peptides sensitized p53-defective cancer cell lines to DNA-damaging agent to death without obvious cytotoxic effect on normal cells. Our results clearly indicate that the specific abrogation of the cell cycle G₂ checkpoint is a feasible strategy for cancer therapy, and hChk1 and Chk2/HuCds1 are proper targets for that purpose.

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