Review Present status of epigenetic drugs in cancer treatment

Epigenetic changes such as promoter specific DNA hypermethylation and histone deacetylation cause tumor suppressor genes to become transcriptionally silent and contribute to malignant transformation. DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors can reactivate silenced genes, block cell cycle and induce cell apoptosis which provides rationale for their use in cancer treatment. DNMT and HDAC inhibitors have therefore emerged as an effective strategy against cancer. Epigenetic modifications have a key role in the pathophysiology of many cancers such as myelodysplastic syndrome (MDS), lymphoma, and leukemia and the use of drugs targeting epigenetic changes has become a topic of intense interest in cancer research. The role of transcriptional repression through epigenetic modulation in carcinogenesis has clinically validated the use of inhibitors of DNMT and HDAC. Epigenetic changes can be pharmacologically reversed resulting in gene re-expression. DNMT inhibitors 5-azacytocine (azacytidine / AZA) and 2’-deoxy-5-azacytidine (decitabine / DAC) are cytosine analogues and are currently the most advanced drugs for epigenetic cancer therapy. AZA and DAC have been approved by FDA for the treatment of MDS. HDAC inhibitors-Vorinostat (SAHA), Romidepsin (depsipeptide FK 219), Belinostat (PXD 101) and LAQ 824/LBH 589 have demonstrated therapeutic benefit in Cutaneous T-cell Lymphoma (CTCL). Both romidepsin and vorinostat are approved by FDA for the treatment of CTCL. In this review, we describe the current status of DNMT inhibitors and HDAC inhibitors usage in cancer treatment and discuss the challenges involved in successful establishment of these novel drugs either alone or in combination therapy for the treatment of various cancers