title: Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes.
abstract: 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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Birgit
authors.initials: B
authors.lastname: Heltweg
authors.forename: Tonibelle
authors.initials: T
authors.lastname: Gatbonton
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schuler
authors.forename: Jeff
authors.initials: J
authors.lastname: Posakony
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Li
authors.forename: Sondra
authors.initials: S
authors.lastname: Goehle
authors.forename: Ramya
authors.initials: R
authors.lastname: Kollipara
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Depinho
authors.forename: Yansong
authors.initials: Y
authors.lastname: Gu
authors.forename: Julian A
authors.initials: JA
authors.lastname: Simon
authors.forename: Antonio
authors.initials: A
authors.lastname: Bedalov
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D051560:Proto-Oncogene Proteins c-bcl-6; D011744:Pyrimidinones / Q000494:pharmacology*; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins / Q000037:antagonists & inhibitors*; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009281:Naphthalenes; D051560:Proto-Oncogene Proteins c-bcl-6; D011744:Pyrimidinones; C495901:TP53 protein, human; D014404:Tubulin; D016159:Tumor Suppressor Protein p53; C510718:cambinol; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins