A small molecule Inauhzin inhibits SIRT1 activity and suppresses tumour growth through activation of p53.
Bottom Line: Here, we report a novel small molecule Inauhzin (INZ) that effectively reactivates p53 by inhibiting SIRT1 activity, promotes p53-dependent apoptosis of human cancer cells without causing apparently genotoxic stress.Moreover, INZ stabilizes p53 by increasing p53 acetylation and preventing MDM2-mediated ubiquitylation of p53 in cells, though not directly in vitro.Hence, our study unearths INZ as a novel anti-cancer therapeutic candidate that inhibits SIRT1 activity and activates p53.
Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.Show MeSH
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Mentions: To validate this possibility, we measured the effect of INZ on SIRT1 activity by conducing in vitro assays using acetylated p53 protein as a substrate and purified His–SIRT1 (Fig S6A and B of Supporting Information) as described in the Experimental Procedures Section of the Supporting Information. As shown in Fig 6A, INZ inhibited SIRT1 deacetylase activity in a dose-dependent fashion and effectively inhibited this activity at 3 µM. This inhibition was specific to INZ and its chemical analogue INZ1 (methyl substituted R1), which activated p53 (Fig 1B and C) and decreased SIRT1 activity in a dose-dependent fashion (Fig S7A of Supporting Information). By contrast, the analogues INZ5 (bromide substituted on R3) and INZ 15 or INZ 18 (lack of G1, data not shown) that failed to induce p53 did not significantly inhibit SIRT1 activity even at the highest concentration we tested (20 µM).
Affiliation: Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, Louisiana, LA, USA.