Current Advances in the Synthesis and Antitumoral Activity of SIRT1-2 Inhibitors by Modulation of p53 and Pro-Apoptotic Proteins

G.      Botta; L.      P. De Santis; R.      Saladino

Abstract

Four different classes of HDACs have been identified in humans so far. Classes I, II and IV are zinc-dependent amidohydrolases, while III is a family of phylogenetically conserved NAD-dependent protein deacetylases/ADP-ribosyltransferase with a welldefined role in modifying chromatin conformation and altering the accessibility of the damaged sites of DNA for repair enzymes. Sirtuins are histone deacetylases (HDACs) of class III that cleave off acetyl groups from acetyl-lysine residues in histones and non-histone proteins. As sirtuins are involved in many physiological and pathological processes, their activity has been associated with different human diseases, including cancer. Especially two sirtuin members, SIRT1 and SIRT2, have been found to antagonize p53-dependent transcriptional activation and apoptosis in response to DNA damage by catalyzing p53 deacetylation. The findings that SIRT1 levels are increased in a number of tumors highlight the oncogenic role of sirtuins, in particular, in the down-modulation of p53 oncosuppressor activity. Along this lane, cancers carrying wild-type (wt) p53 protein are known to deregulate its activity by other mechanisms. Therefore, inhibition of SIRT1 and SIRT2, aimed at restoring wt-p53 transcriptional activity in tumors that retain the ability to express normal p53, might represent a valid therapeutic cancer approach specially when combined with standard therapies. This review will be focused on sirtuin inhibitors, with a specific attention on inhibitors of SIRT1 and SIRT2. Among them, nicotinamide and its analogs, sirtinol, A3 and M15, splitomicin, HR73 and derivatives, cambinol and derivatives, EX 527, kinase inhibitors, suramin, 4-dihydropyridine derivatives, tenovins, TRIPOS 360702, AC 93253, 3-arylideneindolinones, CSC8 and CSC13 will also be described.

Keywords: Antitumoral activity, sirtuin, inhibitors, SIRT1, SIRT2

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