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Cancer Res. 2003 Jan 1;63(1):31-5.

The protein kinase C inhibitor Gö6976 is a potent inhibitor of DNA damage-induced S and G2 cell cycle checkpoints.

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  • 1Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.


In response to DNA damage, cells arrest progression through the cell cycle at either G(1), S, or G(2). We have reported that UCN-01 (7-hydroxystaurosporine) abrogates DNA damage-induced S and G(2) arrest and enhances cytotoxicity selectively in p53 mutant cells, thus providing a potential, tumor-targeted therapy. Unfortunately, UCN-01 binds avidly to human plasma proteins, limiting bioavailability. Because UCN-01 also inhibits protein kinase C (PKC), we screened other PKC inhibitors, expecting them to be unable to abrogate arrest. However, Gö6976 potently abrogated S and G(2) arrest and enhanced the cytotoxicity of the topoisomerase I inhibitor SN38 only in p53-defective cells. Importantly, Gö6976 was nearly as potent at abrogating S and G(2) arrest in human serum, a property not possessed by UCN-01. Cell viability studies demonstrated that Gö6976 was impressively nontoxic as a single agent. Analysis of proteins that regulate cell cycle arrest suggested that both drugs inhibit the checkpoint kinases Chk1 and/or Chk2. Additionally, Gö6976 abrogated S and G(2) arrest at a concentration substantially lower than that required to inhibit PKC; UCN-01 did not demonstrate this selectivity for checkpoint inhibition. These properties make Gö6976 a promising candidate for preclinical and clinical studies.

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