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

Article Details

Citation

Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S, Kollipara R, Depinho RA, Gu Y, Simon JA, Bedalov A

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

Cancer Res. 2006 Apr 15;66(8):4368-77. doi: 10.1158/0008-5472.CAN-05-3617.

PubMed ID
16618762 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
CambinolNAD-dependent protein deacetylase sirtuin-1ProteinHumans
Yes
Inhibitor
Details
CambinolNAD-dependent protein deacetylase sirtuin-2ProteinHumans
Yes
Inhibitor
Details
CambinolNAD-dependent protein deacylase sirtuin-5, mitochondrialProteinHumans
No
Inhibitor
Details