Title:DNA Methyltransferase-1 Inhibitors as Epigenetic Therapy for Cancer
Volume: 13
Issue: 4
Author(s): Varinder Singh, Prince Sharma and Neena Capalash
Affiliation:
Keywords:
Cancer, DNA methylation, methylation inhibition, reexpression, therapy, tumor suppressor genes.
Abstract: DNA methylation is an epigenetic modification involved in gene expression regulation. In cancer, the DNA
methylation pattern becomes aberrant, causing an array of tumor suppressor genes to undergo promoter hypermethylation
and become transcriptionally silent. Reexpression of methylation silenced tumor suppressor genes by inhibiting the DNA
methyltransferases (DNMT1, DNMT3A, and DNMT3B) has emerged as an effective strategy against cancer. The
expression of DNA methyltransferase 1 (DNMT1) being high in S-phase of cell cycle makes it a specific target for
methylation inhibition in rapidly dividing cells as in cancer. This review discusses nucleoside analogues (azacytidine,
decitabine, zebularine, SGI-110, CP-4200), non-nucleoside ihibitors both synthetic (hydralazine, RG108, procaine,
procainamide, IM25, disulfiram) and natural compounds (curcumin, genistein, EGCG, resveratrol, equol, parthenolide)
which act through different mechanisms to inhibit DNMTs. The issues of bioavailability, toxicity, side effects,
hypomethylation resistance and combinatorial therapies have also been highlighted.
