SIRT1/2 Inhibitor IV is a cell-permeable inhibitor of SIRT1 and SIRT2 with IC50 values of 56 μM and 59 μM, respectively [1].
Sirtuin proteins are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases. They play important roles in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein. SIRT1 and SIRT2 exist in both the nucleus and cytoplasm. SIRT1 regulate pathways in metabolism, inflammation and tumorigenesis and SIRT2 functions as a tubulin deacetylase [1][2].
SIRT1/2 Inhibitor IV (Cambinol) is a cell-permeable sirtuin inhibitor that inhibits human SIRT1 and SIRT2 NAD+-dependent deacetylase activity with IC50 values of 56 μM and 59 μM, respectively, and has only weak inhibitory activity against SIRT5 (42% inhibition at 300 μmol/L). In NCI H460 lung cancer cell line, Cambinol inhibited SIRT1 and SIRT2 deacetylase activity, and also increased p53 activation during DNA damage response [1]. In HepG2 cells, Cambinol inhibited SIRT activity, which led to a dose-dependent repression of HIF-1a protein accumulation [2].
In nonobese diabetic/severe combined immunodeficient mice xenografted Daudi cells, cambinol at the dose of 100 mg/kg reduced tumor growth without inducing obvious toxicity [1].
References:
[1]. Heltweg B, Gatbonton T, Schuler AD, et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 2006 Apr 15;66(8):4368-77.
[2]. Laemmle A, Lechleiter A, Roh V, et al. Inhibition of SIRT1 impairs the accumulation and transcriptional activity of HIF-1α protein under hypoxic conditions. PLoS One. 2012;7(3):e33433.