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The Radiosensitizing Agent 7-Hydroxystaurosporine (UCN-01) Inhibits the DNA Damage Checkpoint Kinase hChk1¹

Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [E. C. B., D. F. L., L. M. K., J. N. S.], and Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710 [R. T. A.]

The investigational anticancer agent 7-hydroxystaurosporine (UCN-01) abrogates the G₂ checkpoint in tumor cells and sensitizes them to the lethal effects of genotoxic anticancer agents. On the basis of the role of the Cdc25C phosphatase in maintenance of this damage-inducible checkpoint, we hypothesized that UCN-01 inhibits a component of the signal transduction pathway that modulates Cdc25C phosphorylation. Of the three kinases known to phosphorylate Cdc25C on Ser²¹⁶, both checkpoint kinase 1 (hChk1) and Cdc25C-associated protein kinase 1 (cTAK1) were potently inhibited by UCN-01 with IC₅₀s of 11 and 27 nM, respectively. Treatment of K562 erythroblastoid leukemia cells with similar drug concentrations resulted in decreased levels of Ser²¹⁶ phosphorylation of Cdc25C and complete disruption of the -radiation-induced G₂ checkpoint. In contrast to hChk1, the hChk2 kinase was 100-fold more resistant to inhibition by UCN-01 (IC₅₀, 1040 nM). These results suggest that disruption of the DNA damage-induced G₂ checkpoint by UCN-01 is mediated through the inhibition of the Cdc25C kinases, hChk1 and cTAK1, and that hChk2 activity is not sufficient to enforce the G₂ checkpoint in cells treated with a pharmacological inhibitor of hChk1.

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				E. A. Sausville, S. G. Arbuck, R. Messmann, D. Headlee, K. S. Bauer, R. M. Lush, A. Murgo, W. D. Figg, T. Lahusen, S. Jaken, et al. Phase I Trial of 72-Hour Continuous Infusion UCN-01 in Patients With Refractory Neoplasms J. Clin. Oncol., April 15, 2001; 19(8): 2319 - 2333. [Abstract] [Full Text] [PDF]

				H. Miyata, Y. Doki, H. Yamamoto, K. Kishi, H. Takemoto, Y. Fujiwara, T. Yasuda, M. Yano, M. Inoue, H. Shiozaki, et al. Overexpression of CDC25B Overrides Radiation-induced G2-M Arrest and Results in Increased Apoptosis in Esophageal Cancer Cells Cancer Res., April 1, 2001; 61(7): 3188 - 3193. [Abstract] [Full Text]

				Y. Hirose, M. S. Berger, and R. O. Pieper p53 Effects Both the Duration of G2/M Arrest and the Fate of Temozolomide-treated Human Glioblastoma Cells Cancer Res., March 1, 2001; 61(5): 1957 - 1963. [Abstract] [Full Text]

				V. Gottifredi, O. Karni-Schmidt, S.-Y. Shieh, and C. Prives p53 Down-Regulates CHK1 through p21 and the Retinoblastoma Protein Mol. Cell. Biol., February 15, 2001; 21(4): 1066 - 1076. [Abstract] [Full Text]

				Z. Shi, A. Azuma, D. Sampath, Y.-X. Li, P. Huang, and W. Plunkett S-Phase Arrest by Nucleoside Analogues and Abrogation of Survival without Cell Cycle Progression by 7-Hydroxystaurosporine Cancer Res., February 1, 2001; 61(3): 1065 - 1072. [Abstract] [Full Text]

				N Rhind and P Russell Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways J. Cell Sci., January 11, 2000; 113(22): 3889 - 3896. [Abstract] [PDF]

				B. Hu, X.-Y. Zhou, X. Wang, Z.-C. Zeng, G. Iliakis, and Y. Wang The Radioresistance to Killing of A1-5 Cells Derives from Activation of the Chk1 Pathway J. Biol. Chem., May 18, 2001; 276(21): 17693 - 17698. [Abstract] [Full Text] [PDF]

				X. Wu, S. R. Webster, and J. Chen Characterization of Tumor-associated Chk2 Mutations J. Biol. Chem., January 19, 2001; 276(4): 2971 - 2974. [Abstract] [Full Text] [PDF]

				D. Curman, B. Cinel, D. E. Williams, N. Rundle, W. D. Block, A. A. Goodarzi, J. R. Hutchins, P. R. Clarke, B.-B. Zhou, S. P. Lees-Miller, et al. Inhibition of the G2 DNA Damage Checkpoint and of Protein Kinases Chk1 and Chk2 by the Marine Sponge Alkaloid Debromohymenialdisine J. Biol. Chem., May 18, 2001; 276(21): 17914 - 17919. [Abstract] [Full Text] [PDF]

				W. A. Cliby, K. A. Lewis, K. K. Lilly, and S. H. Kaufmann S Phase and G2 Arrests Induced by Topoisomerase I Poisons Are Dependent on ATR Kinase Function J. Biol. Chem., January 4, 2002; 277(2): 1599 - 1606. [Abstract] [Full Text] [PDF]

				P. B. Deming, C. A. Cistulli, H. Zhao, P. R. Graves, H. Piwnica-Worms, R. S. Paules, C. S. Downes, and W. K. Kaufmann The human decatenation checkpoint PNAS, October 9, 2001; 98(21): 12044 - 12049. [Abstract] [Full Text] [PDF]