Rational Development of Histone Deacetylase Inhibitors as Anticancer Agents: A Review

Abstract

The epigenome is defined by DNA methylation patterns and the associated post-translational modifications of histones. This histone code determines the expression status of individual genes dependent upon their localization on the chromatin. The histone deacetylases (HDACs) play a major role in keeping the balance between the acetylated and deacetylated states of chromatin and eventually regulate gene expression. Recent developments in understanding the cancer cell cycle, specifically the interplay with chromatin control, are providing opportunities for developing mechanism-based therapeutic drugs. Inhibitors of HDACs are under considerable exploration, in part because of their potential roles in reversing the silenced genes in transformed tumor cells by modulating transcriptional processes. This review is an effort to summarize the nonclinical and clinical status of HDAC inhibitors currently under development in anticancer therapy.In eukaryotic cells, DNA has been conserved over evolution in a condensed and densely packed higher order structure called chromatin. Chromatin, present in the interphase nucleus, is composed of regular repeating units of nucleosomes, which represent the principal protein-nucleic acid relationship. The major components of chromatin are nucleic acids (DNA and RNA), which are negatively charged; associated proteins, including histones, that are positively charged at neutral pH; and nonhistone chromosomal proteins, which are acidic at neutral pH. Within the nucleus, chromatin can exists in two different forms: heterochromatin, which is highly compact and transcriptionally inactive, or euchromatin, which is loosely packed and accessible to RNA polymerases for involvement in transcriptional processes and gene expression. A nucleosome is a complex of 146 nucleotide base pairs of DNA wrapped around the core histone octamer that helps organize chromatin. The histone octamer is composed of two copies each of H2A, H2B, H3, and H4 proteins, which are very basic, mainly because of positively charged amino-terminal side chains rich in the amino acid lysine. Post-translational and other changes in chromatin, such as acetylation/deacetylation at lysine residues, methylation at lysine or arginine residues, phosphorylation at serine resides, ubiquitylation at lysines, and/or ADP ribosylation, are mediated by chemical modification of various sites on N-terminal tail .The structural modification of histones is regulated mainly by acetylation/deacetylation of the N-terminal tail and is crucial in modulating gene expression, because it affects the interaction of DNA with transcription-regulatory non-nucleoArticle, publication date, and citation information can be found at

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

“…Furthermore, an increase in p21 WAF1/CIP1 (hereafter referred to as p21), the cyclin-dependent kinase inhibitor, was observed. This is especially important since p21 has been known to be involved in the ability of HDACIs to block proliferation (Acharya et al, 2005). p21 protein expression was found to be upregulated (9.25-fold) with MS-275 alone and even more (10-fold) in the combination of VN/66-1 and MS-275 ( Figure 3D).…”

HDAC4 represses p21WAF1/Cip1 expression in human cancer cells through a Sp1-dependent, p53-independent mechanism

“…The recent FDA approval of SAHA (Zolinza) for treatment of cutaneous T-cell lymphoma (Duvic and Vu, 2007a, b) validates the concept of HDAC inhibition in the treatment of cancer. HDAC inhibitors exert multiple and desirable anticancer effects by modulating the expression of the subset of genes involved in the inhibition of tumor cell proliferation, and differentiation, induction of apoptosis and inhibition of angiogenesis (Marks et al, 2004;McLaughlin and La Thangue, 2004;Acharya et al, 2005;Kelly and Marks, 2005;Bolden et al, 2006;Minucci and Pelicci, 2006;Dokmanovic et al, 2007;Rasheed et al, 2007;Xu et al, 2007).…”

Raf kinases: Oncogenesis and drug discovery

“…165,166 Although histones are the primary targets of HDACs and transcriptional reactivation of ''dormant'' tumor-suppressor genes is clearly one major mechanism of action, other cellular targets and pleiotropic effects have been described. 167 In context with Raf kinases, HDAC inhibitors seem to have 2 ways of action: (i) in human multiple myeloma C-RAF mRNA expression was substantially reduced in response to treatment with the HDAC inhibitor SAHA 168 and (ii) in human leukemia cell lines it was shown that HDAC inhibitors such as LAQ824 induce acetylation and inactivation of HSP90 which in turn promotes degradation of HSP90 client proteins including C-RAF.…”