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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Clinical Research and 2 Human Biology Divisions, Fred Hutchinson Cancer Research Center; Departments of 3 Medicine and 4 Radiation Oncology and Immunology, University of Washington, Seattle, Washington; and 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Departments of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts
Requests for reprints: Antonio Bedalov, Clinical Research Division, Fred Hutchinson Cancer Research Center, D2-100, 1100 Fairview Avenue North, Seattle WA 98109. Phone: 206-667-4863; Fax: 206-667-5669; E-mail: abedalov{at}fhcrc.org.
SIRT1 and other NAD-dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein. Hereby, we describe the identification of a compound we named cambinol that inhibits NAD-dependent deacetylase activity of human SIRT1 and SIRT2. Consistent with the role of SIRT1 in promoting cell survival during stress, inhibition of SIRT1 activity with cambinol during genotoxic stress leads to hyperacetylation of key stress response proteins and promotes cell cycle arrest. Treatment of BCL6-expressing Burkitt lymphoma cells with cambinol as a single agent induced apoptosis, which was accompanied by hyperacetylation of BCL6 and p53. Because acetylation inactivates BCL6 and has the opposite effect on the function of p53 and other checkpoint pathways, the antitumor activity of cambinol in Burkitt lymphoma cells may be accomplished through a combined effect of BCL6 inactivation and checkpoint activation. Cambinol was well tolerated in mice and inhibited growth of Burkitt lymphoma xenografts. Inhibitors of NAD-dependent deacetylases may constitute novel anticancer agents. (Cancer Res 2006; 66(8): 4368-77)
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