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Beschreibung

A cell-permeable phenothiazine derivative that selectively inhibits SirT1 (IC50 <=2.0 µ,M), but not SirT2, SirT3, or HCAC8 (IC50 >50 µ,M), activity. Effectively elevates cellular p53 lysine acetylation (Effective conc. 2 µ,M), thereby protecting p53 lysine residues from MDM2-mediated ubiquitination without inhibiting MDM2 activity toward deacetylated p53. Shown to inhibit cancer cell growth in a p53-dependent manner (IC50 = 2.0 and 15.7µ,M, respectively, against HCT116p53+/+ and HCT116p53-/- cells) and synergize with Nutlin-3 (Cat. Nos. 444143, 444151, & 444152) in blocking HCT116p53+/+ proliferation in vitro (1 µ,M INZ & 4 µ,M Nutlin-3) and inducing HCT116p53+/+ apoptosis in mice in vivo (15 mg INZ/kg/d i.p, 150 mg Nut-3/kg/12 h p.o.)., A cell-permeable phenothiazine derivative that selectively inhibits SirT1 (IC50 <=2.0 µ,M), but not SirT2, SirT3, or HCAC8 (IC50 >50 µ,M), activity and effectively elevates cellular p53 lysine acetylation (Effective conc. 2 µ,M), thereby protecting p53 lysine residues from MDM2-mediated ubiquitination without directly inhibiting MDM2 function per se or its activity toward deacetylated p53. Shown to inhibit cancer cell growth in a p53-dependent manner (IC50 = 2.0 and 15.7µ,M, respectively, against HCT116p53+/+ and HCT116p53-/- cells) and synergize with Nutlin-3 (Cat. Nos. 444143, 444151, & 444152) in blocking HCT116p53+/+ proliferation in vitro (by 29%, 76%, and >98, respectively, with 1 µ,M INZ alone, 4 µ,M Nutlin-3 alone, or in combination) and inducing HCT116p53+/+ apoptosis in mice in vivo (3.5% above control TUNEL staining with either drug treatment alone or 25% with combined treatment, 15 mg INZ/kg via daily i.p, 150 mg Nut-3/kg b.i.d. p.o.).