SRT1720

SRT1720 is a selective small molecule activator of SIRT1 that is 1,000-fold more potent than resveratrol (EC1.5 = 0.16 versus 46.2 µM, respectively). SIRT1 belongs to the silent information regulator 2 (Sir2) protein family of enzymes and functions as a NAD(+) -dependent class III histone deacetylase. Treatment of MM cells with SRT1720 inhibited growth and induced apoptosis in MM cells resistant to conventional and bortezomib therapies without significantly affecting the viability of normal cells. Mechanistic studies showed that anti-MM activity of SRT1720 is associated with: (i) activation of caspase-8, caspase-9, caspase-3, poly(ADP) ribose polymerase; (ii) increase in reactive oxygen species; (iii) induction of phosphorylated ataxia telangiectasia mutated/checkpoint kinase 2 signalling; (iv) decrease in vascular endothelial growth factor-induced migration of MM cells and associated angiogenesis; and (v) inhibition of nuclear factor-κB. Blockade of ATM attenuated SRT1720-induced MM cell death. Finally, SRT1720 enhanced the cytotoxic activity of bortezomib or dexamethasone.