Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2′-deoxycytidine

Abstract

DNA cytosine methylation plays a considerable role in normal development, gene regulation, and carcinogenesis. Hypermethylation of the promoters of some tumor suppressor genes and the associated silencing of these genes often occur in certain cancer types. The reversal of this process by DNA methylation inhibitors is a promising new strategy for cancer therapy. In addition to the four wellcharacterized nucleoside analogue methylation inhibitors, 5-azacytidine, 5-aza-2V -deoxycytidine (5-Aza-CdR), 5-fluoro-2V -deoxycytidine, and zebularine, there is a growing list of non-nucleoside inhibitors. However, a systemic study comparing these potential demethylating agents has not been done. In this study, we examined three non-nucleoside demethylating agents, (À)-epigallocatechin-3-gallate, hydralazine, and procainamide, and compared their effects and potencies with 5-Aza-CdR, the most potent DNA methylation inhibitor. We found that 5-Aza-CdR is far more effective in DNA methylation inhibition as well as in reactivating genes, compared with non-nucleoside inhibitors. [Mol Cancer Ther 2005;4(10):1515 -20]

Epigenetic cancer therapy: rationales, targets and drugs

“…Small molecules that selectively inhibit individual DNMT enzymes in biochemical assays have been described recently (Kuck et al, 2010) and the development of enzyme-specific inhibitors thus appears feasible. However, even though we have seen a rapid increase in the number of candidate DNMT inhibitors over the past few years, the epigenetic potency of 5-azacytidine and decitabine presently remains unmatched (Chuang et al, 2005;Stresemann et al, 2006;MedinaFranco et al, 2011). Moreover, the known smallmolecule DNMT inhibitors would require a substantial amount of preclinical development before competitive clinical candidates are likely to emerge.…”

Demethylation of a LINE-1 antisense promoter in the cMet locus impairs Met signalling through induction of illegitimate transcription

“…This reversibility established the use of DNA methyltransferase (DNMT) inhibitors as an attractive concept for cancer therapy (Lyko and Brown, 2005). The cytosine analogues 5-azacytidine (azacytidine) and 5-aza-2 0 -deoxycytidine (decitabine) function as DNMT inhibitors and have been shown to effectively demethylate DNA and reverse gene silencing in vitro (Chuang et al, 2005;Stresemann et al, 2006). In addition, azanucleosides are currently the most advanced drugs for epigenetic cancer therapy (Egger et al, 2004;Issa and Kantarjian, 2009).…”

“…Therefore, decitabine-and azacytidine-induced demethylation is a passive mechanism linked to the DNA replication process, thus affecting only dividing cells, such as highly proliferating cancer cells. In cell culture models, both drugs have the ability to reduce cytosine methylation significantly, although the efficiency can vary between cell lines (Chuang et al, 2005;Stresemann et al, 2006). Several studies also showed genome-wide and gene-specific demethylating activity of azanucleoside drugs in myelodysplastic syndrome patients undergoing epigenetic therapy (Mund et al, 2005;Gore et al, 2006;Yang et al, 2006;Stresemann et al, 2008).…”

Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells

“…Pharmacological inhibitors of DNMT1 [5-azacytidine (5-aza-CR) and its deoxy analog, 5-aza-2Ј-deoxycytidine (5-aza-CdR)] get incorporated into newly-synthesized DNA (12,13). Once incorporated into DNA, these compounds form covalent complexes with DNMTs, thereby depleting active enzymes (14,15) and activating gene expression (16). Recently, 5-aza-CdR-induced depletion of DNMT1 was shown to be mediated by proteasomal pathways in mammalian nuclei (17).…”