Nucleosidic DNA demethylating epigenetic drugs - A comprehensive review from discovery to clinic
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't, Review
PubMed
29454856
DOI
10.1016/j.pharmthera.2018.02.006
PII: S0163-7258(18)30031-7
Knihovny.cz E-resources
- Keywords
- Combinatorial therapy, DNA hypermethylation, DNA methyltransferase inhibitors, Drug resistance, Gene silencing, Nucleoside analogs,
- MeSH
- Antineoplastic Agents pharmacology therapeutic use MeSH
- Azacitidine analogs & derivatives pharmacology MeSH
- Drug Resistance, Neoplasm MeSH
- DNA (Cytosine-5-)-Methyltransferase 1 antagonists & inhibitors MeSH
- Humans MeSH
- DNA Methylation drug effects MeSH
- Nucleosides pharmacology MeSH
- Drug Discovery * MeSH
- Thioguanine pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Names of Substances
- Antineoplastic Agents MeSH
- Azacitidine MeSH
- DNA (Cytosine-5-)-Methyltransferase 1 MeSH
- guadecitabine MeSH Browser
- Nucleosides MeSH
- Thioguanine MeSH
DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development. This review is a comprehensive report of the literature published in past 40 years, on so far discovered nucleosidic DNA methylation inhibitors in chronological order. The review will provide a complete insight to the readers about the mechanisms of action, efficacy to demethylate and re-express various cancer-related genes, anti-tumor activity, cytotoxicity profile, stability, and bioavailability of these drugs. The review further presents the far known mechanisms of primary and secondary resistance to azanucleoside drugs. Finally, the review highlights the ubiquitous role of DNA hypomethylating epi-drugs as chemosensitizers and/or priming agents, and recapitulate the combinatorial cancer preventive effects of these drugs with other epigenetic agents, conventional chemo-drugs, or immunotherapies. This comprehensive review analyzes the beneficial characteristics and drawbacks of nucleosidic DNA methylation inhibitors, which will assist the pre-clinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy.
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