EX 527 is a potent and selective inhibitor of the SIRT1 class III histone deacetylase enzyme. EX 527 has been used a powerful tool for studying the relationship between SIRT1 and cell regulation. The deacetylation of cortactin, a protein responsible for rearrangements of the actin cytoskeleton, is associated with cell motility and possibly tumorigenesis, and blocking of this deacetylation by EX 527 correlated to a decrease in cell motility. Blocking of SIRT1 by EX 527 also demonstrated that deacetylation of the important tumor suppressor protein p53 is mediated by SIRT1 as well.
|Cell lines||NCI-H460 cells, MCF-7 cells, U-2 OS cells, or HMEC cell lines|
|Preparation method||Cell viability assay. NCI-H460 cells, MCF-7 cells, U-2 OS cells, or HMEC were plated at 2,000 cells per well in opaque-walled 96-well plates (Corning) for the viability assay and 800 cells per well in 96-well Cytostar-T scintillating microplates (Amersham) for the proliferation assay. Cells were incubated for 1 day (NCI-H460) or 2 days (MCF-7, U-2 OS, and HMEC) prior to exposure to DNA-damaging agents and deacetylase inhibitors. All experiments were performed in triplicate.For viability assays, cells were treated with the indicated compounds for 48 h. Cell viability was then determined using the Cell Titer-Glo luminescent assay (Promega), which measures total ATP levels as an index of cell number. Luminescence was measured on a Luminoskan Ascent (ThermoLabSystems).|
|Incubation time||48 h|
|Animal models||Male Sprague-Dawley rats (8 weeks old, 200–250 g) and C57/B6 mice (8 weeks old) model|
|Dosages||5-10 μg in a total volume of 5 μL|
|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.
Activating transcription factor 4 confers a multidrug resistance phenotype to gastric cancer cells through transactivation of SIRT1 expression.
Zhu et al. PLoS One. 2012;7(2):e31431. PMID: 22363646.
The central Sirtuin 1/p53 pathway is essential for the orexigenic action of ghrelin.
Velásquez DA, et al. Diabetes. 2011 Apr;60(4):1177-85. PMID: 21386086.
Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage.
Solomon JM, et al. Mol Cell Biol. 2006 Jan;26(1):28-38. PMID: 16354677.
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