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Department of Cancer Pharmacology, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan 48105 [A. J. K., B. G. H., J. M., R. L. M.], and Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908 [C. A. M., C. D. A.]
1 To whom requests for reprints should be addressed, at Cancer Pharmacology, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105. Phone: (734) 622-7759; Fax: (734) 622-7158; E-mail: Alan.Kraker{at}pfizer.com
CI-994 or N-acetyldinaline [4-(acetylamino)-N-(2-amino-phenyl) benzamide] is an antitumor cytostatic agent currently undergoing clinical trial. Although several changes in cellular metabolism induced by the drug have been characterized, the primary molecular mechanism of its antitumor activity has been previously unknown. Here, we show that CI-994 is a histone deacetylase (HDAC) inhibitor that causes histone hyperacetylation in living cells. In assays of isolated enzymes, CI-994 inhibited HDAC-1 and HDAC-2 in a concentration-dependent fashion but had no effect on the activity of the prototypical histone acetyltransferase GCN5. Acetylated histone H3-specific Western blots were used to monitor histone acetylation in HCT-8 colon carcinoma cells treated with CI-994 in vitro. CI-994 induced hyperacetylation of H3 in a time- and dose-dependent fashion. H3 hyperacetylation was detectable as early as 30 min after the addition of CI-994 to cells. These data demonstrate that inhibition of HDAC is an early event in cells treated with CI-994 and suggest that this inhibition is mechanistically related to the antitumor activity of this compound.
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