Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes

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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2006-04, Vol.66 (8), p.4368-4377
Main Authors: HELTWEG, Birgit, GATBONTON, Tonibelle, BEDALOV, Antonio, SCHULER, Aaron D, POSAKONY, Jeff, HONGZHE LI, GOEHLE, Sondra, KOLLIPARA, Ramya, DEPINHO, Ronald A, YANSONG GU, SIMON, Julian A
Format: Article
Language:English
Subjects:
Acetylation - drug effects
Animals
Antineoplastic agents
Antineoplastic Agents - pharmacology
Biological and medical sciences
Burkitt Lymphoma - drug therapy
Burkitt Lymphoma - enzymology
Burkitt Lymphoma - metabolism
Cell Line, Tumor
DNA-Binding Proteins - metabolism
Enzyme Inhibitors - pharmacology
Histone Deacetylase Inhibitors
Humans
Medical sciences
Mice
Naphthalenes - pharmacology
Pharmacology. Drug treatments
Proto-Oncogene Proteins c-bcl-6
Pyrimidinones - pharmacology
Sirtuin 1
Sirtuin 2
Sirtuins - antagonists & inhibitors
Tubulin - metabolism
Tumor Suppressor Protein p53 - metabolism
Tumors
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-05-3617