New histone acetylation/deacetylation specific inhibitors: a novel and potential approach to cancer therapy

Abstract

The acetylation status of histones is regulated in eukaryotes by two kinds of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs), which are responsible for acetylation and deacetylation of lysines residues in N-terminal tails of histone.[1] Thus acetylation, together with phosphorylation and methylation of N-terminal tail of histones, are involved in regulating fundamental processes, such as proliferation and cell death.[2-3] Sodium butyrate, which belongs together with valproic acid to the class of short chain fatty acids, was the first HDAC inhibitor (HDACI) to be identified.[1] Organotin compounds have various influences on physical function including the hormone and immune systems, embryogenesis, and development. Dibutyltin and diphenyltin, metabolites of TBT and TPT, respectively, also promoted HAT activity.[4] New triorganotin(IV) complexes of valproic acid have been synthesized and investigated by spectroscopical and biological methods. An anionic, monodentate valproate ligand was observed, ester-like coordinating the tin atom on a tetra-coordinated, monomeric environment. The structures, though, can distort towards a pentacoordination, as a consequence of a long range O-Sn interaction. Crystallographic and NMR findings confirm this situation both in solid state and solution. Biological finding evidenced a clear cytotoxic action of the complexes in hepatocellular carcinoma cell cultures: one of the complexes induced an 80% cell viability reduction after 24 h treatment in HepG2 cells. This effect was accompanied by the appearance of biochemical signs of apoptosis. In Chang liver cells, the same compound induced only modest effects, suggesting a potential use as anti-cancer drug.