DNA Hypomethylating Drugs in Cancer Therapy

Abstract

Aberrant DNA methylation is a critically important modification in cancer cells, which, through promoter and enhancer DNA methylation changes, use this mechanism to activate oncogenes and silence of tumor-suppressor genes. Targeting DNA methylation in cancer using DNA hypomethylating drugs reprograms tumor cells to a more normal-like state by affecting multiple pathways, and also sensitizes these cells to chemotherapy and immunotherapy. The first generation hypomethylating drugs azacitidine and decitabine are routinely used for the treatment of myeloid leukemias and a next-generation drug (guadecitabine) is currently in clinical trials. This review will summarize preclinical and clinical data on DNA hypomethylating drugs as a cancer therapy.

Depletion of ZBTB38 potentiates the effects of DNA demethylating agents in cancer cells via CDKN1C mRNA up-regulation

“…5-azacytidine and decitabine have been used to improve survival and health quality of patients with myelodysplastic syndromes (MDS), acute myelogenous leukemia (AML) and chronic myelomonocytic leukemia (CMML) 4 – 6 . Nonetheless, due to their incorporation into the DNA and the formation of DNA adducts these drugs may have unwanted side effects, limiting their clinical applications 4 , 7 . There is thus need to develop new therapeutic strategies (i.e., new DNMT inhibitors) and to identify biomarkers that may help predict which patient will most benefit from DNMTi therapy.…”

“…At the transcriptional level, expression of PLBC1 , BCL2L10 or micro-RNA-126 influence the response to DNMTi 18 – 20 . Furthermore, the efficacy of 5-azacytidine can be further enhanced by combination with other compounds including histone deacetylase inhibitors (HDACi) 1 , 4 , 7 , 21 .…”

Decitabine induces regulatory T cells, inhibits the production of IFN-gamma and IL-17 and exerts preventive and therapeutic efficacy in rodent experimental autoimmune neuritis

“…Decitabine (DAC, 5-aza-2′-deoxycytidine) is a hypomethylating drug currently used for the treatment of myelodisplastic syndrome and is currently gaining much attention for its use in other forms of blood cancer, including acute myeloblastic leukemia (Gardin and Dombret, 2017;Sato et al, 2017), as well as solid cancer (Linnekamp et al, 2017). Recent studies have also shown that DAC possesses potent immunomodulatory properties through different pharmacological mechanisms, that entail induction of regulatory T cells and shift of the Th1-Th17/Th2 cytokine balance, in favor of the latter, with consequential promotion of an anti-inflammatory mileau.…”

Antitumor synergy with SY-1425, a selective RARα agonist, and hypomethylating agents in retinoic acid receptor pathway activated models of acute myeloid leukemia

“…This then results in loss of DNMT1, as the DNA-protein adduct is degraded by the DNA damage response pathway. 9 After loss of haematologica 2019; 104:e138 LETTERS TO THE EDITOR Figure 1. SY-1425 and hypomethylating agents had synergistic antiproliferative activity in RARA-high and IRF8-high cells.…”

“…A B C DNMT1, the cell cannot maintain its methylation enabling re-initiation of cellular differentiation pathways and induction of proliferative arrest. 5,9,10 We recently demonstrated that super-enhancer (SE) analysis can define novel epigenomic subtypes of non-APL AML. In non-APL AML, RARA pathway activation, detected by the presence of SEs at the RARA or IRF8 gene loci, was found to be predictive of response to SY-1425 in preclinical models, establishing the potential for biomarker-guided clinical studies.…”