Sirtinol

Sirtinol is a specific NAD-dependant class III histone deacetylase sirtuin inhibitor targeting human Sirt1 and Sirt2 with IC50 of 131 μM and 38 μM, respectively. Sirtinol is slightly less potent against recombinant yeast Sir2p with IC50 of 68 μM. Sirtinol does not affect HDAC1 activity at 50 μM, suggesting that it specifically inhibits sirtuin deacetylase activity. Unlike TSA, Sirtinol treatment does not cause HeLa cells to change from a rounded morphology to a flattened morphology. Consistently, TSA causes robust acetylation of histones H3 and H4, as well as α-tubulin, whereas Sirtinol does not produce any of these effects. Treatment with Sirtinol inhibits body-axis formation and vascularization in Arabidopsis. Although Sirtinol (100 μM) has no axonal toxicity on uninjured axons, it effectively blocks NAD-dependent axonal protection (NDAP) after transection, indicating that Sirt1 proteins are likely effectors of this process. Sirtinol significantly increases mononucleosomes and oligonucleosomes in the cytoplasm of cardiac myocytes, a sensitive marker of apoptosis, and induces cleavage of caspase-3 almost equally as H2O2. [3] Sirtinol induces senescence-like growth arrest in human breast cancer MCF-7 cells and lung cancer H1299 cells, characterized by induction of senescence-associated β-galactosidase activity and increased expression of plasminogen activator inhibitor 1 Sirtinol-induced senescence-like growth arrest is accompanied by impaired activation of Ras-MAPK pathways but not Akt/PKB in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Similar to Nicotinamide, Sirtinol inhibits the growth of MiaPaAa-2, BxPC-3, SOJ-6, and HeLa cells with IC50 of 48.1 μM, 48.5 μM, 48.4 μM, 53.9 μM, respectively.