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.
|Cell lines||4T1 cells|
|Preparation method||Cell viability assay.
One day before treatment, 1.5x104 cells per well were seeded in a 96-well plate and allowed to attach overnight. The cells were then treated with varying concentrations of SRT1720 for 24 h. The viable cell number was determined with an MTS assay kit (Promega, Madison, WI, USA).
|Incubation time||24 h|
|Animal models||4T1 cells tumor-bearing mice model|
|Dosages||100 mg/kg 5 times per week|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥100 mg/mL|
SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice.
Suzuki K, et al. Oncol Rep. 2012 Jun;27(6):1726-32. PMID: 22470132.
SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator.
Dai H, et al. J Biol Chem. 2010 Oct 22;285(43):32695-703. PMID: 20702418.
SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.
Pacholec M, et al. J Biol Chem. 2010 Mar 12;285(11):8340-51. PMID: 20061378.
Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.
Milne JC, et al. Nature. 2007 Nov 29;450(7170):712-6. PMID: 18046409.
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