Table 4.
Current DNMTi and DNMT-HDAC dual inhibitors repurposed drugs with applications in cancer therapy [*modified from Moreira-Silva et al. (9)].
| Class | Compound | First indication | Epigenetic target | Drug-target interaction | Cancer model/New indication | Key features in mechanism | References |
|---|---|---|---|---|---|---|---|
| Section 1. DNMT inhibitors | |||||||
| Non-nucleoside analogs | Hydralazine | Anti-hypertensor | DNMT1 | Four high-affinity interaction points with DNMT1 through the residues Lys 162 and Arg 240 within the enzyme active site. | T‐Cell Leukemia cells | Increases LFA-1 expression inhibits T Cells ERK pathway phosphorylation, decreases DNMT enzyme activity, and decreases DNMT1 and DNMT3A protein levels. Reduces de novo methylation due to greater affinity to hemi methylated substrates (target of DNMT1),. | (156, 166) |
| Breast Cancer cells | In vivo induces DNA demethylation and increases expression of ER as well as RARb, p12 and p16 in vitro. | (167) | |||||
| Bladder Cervical Cancer cells | (157) | ||||||
| Prostate Cancer cells | Increases apoptosis, inhibits RGFR pathway, thus induces cell cycle arrest. Decreases DNMT1, DNMT3a and b protein levels. Upregulates p21 which decreases promoters DNA methylation and induces histone acetylation. | (156) | |||||
| Cervical Cancer cells | Induces APC expression, inhibits cell growth, induces cell cycle arrest and apoptosis. Promotes DNA demethylation. | (158) | |||||
| Disulfiram (DSF) | Alcohol aversive | DNMT1 | DSF could interfere with the catalytic activity of DNMT1 by reacting with a citosine ring via thiol group of catalytic site of DNMT1. | Prostate Cancer cells | Reduces global 5mC content, through inhibition of DNMT1 activity on hemimethylated substrates. Decreases methylation in APC and RARB gene promoters, thus increasing re-expression. Inhibits growth and clonogenic survival of prostate cancer cell lines. | (70) | |
| Procainamide | Cardiac arrythmias | DNMT1 | Partially competitive inhibitor of DNMT1 that interacts with the binding pocket of the enzyme | Prostate Cancer cells | Promotes GSTP1 CpG island hypomethylation, thus induces GSTP1 re-expression in LNCaP cells in vitro and in in vivo assays | (168) | |
| Breast Cancer cells | Induces DNA demethylation increases expression of ER RARb; also induces re-expression of p12 and p16 (in vitro). | (169) | |||||
| Colon Cancer cells | Greatly reduces affinity for hemi-methylated DNA and SAM in catalysis, reduces global 5mC content, thus reduces gene-specific hypermethylation at promoter CpG islands. | (154) | |||||
| Non-small Cell Lung Cancer cells | Inhibits DNMT activity and decreases promoter demethylation of WIF-1, restoring WIF-1 expression, thus downregulating the Wnt pathway | (169) | |||||
| Procaine (PCA) | Anesthesic for spinal block | DNMT1, DNMT3A | Interacts with the binding pocket of the enzyme inhibiting catalytic activity (non-nucleoside), | Breast Cancer cells | Demethylates densely hypermethylated CpG islands, reduces 5mC DNA content by 40%, restoring gene expression of RARβ2, and has growth-inhibitory effects, causing mitotic arrest | (153) | |
| Gastric Cancer cells | Inhibits DNMT1 and 3A activity through molecular docking in the catalytic binding site, disrupting the binding of DNMT to DNA. Reduces proliferation, induces apoptosis, and restores expression of CDKN2A and RARb | (152) | |||||
| Hepatocellular Carcinoma cells | DNA demethylation and silenced gene reactivation of p16, HAI-2/PB, and NQO1. Promotes cell cycle arrest and reduces viability. Also shown significant reduction in tumor volume in vivo. | (170) | |||||
| Non-small Cell Lung Cancer cells | Inhibits DNMT activity, causing promoter demethylation of WIF-1, thus restores WIF-1 expression and downregulation of Wnt pathway | (169) | |||||
| Antibiotic | Nanaomycin A | Anthracycline antibiotic | DNMT3B | Interaction with active site of DNMT3B in specific a.a. (Glu697 Arg731 Arg733) of enzyme binding pocket, thus promoting a molecular docking in DNMT3B that inhibits enzymatic activity | Colon Cancer cells | Decreases DNMT1, 3A, 3B expression. Inhibits DNMT3B activity promoting reactivation of RASSF1A. Reduces cell proliferation and viability | (164) |
| Lung Cancer cells | |||||||
| Bone marrow cells | |||||||
| Mithramycin A (MMA) | Hypercalcemia drug, and antineoplastic agent | DNMT1 | Possibly interferes with DNMT1 binding at the CpG region in TSG promoters through binding DNMT1 protein or might be a form a complex between MMA, DNMT1 and double-stranded DNA |
Lung Cancer cells | Inhibits DNMT1 activity and decreases protein level. Decreases CpG methylation on SLIT2 and TIMP-3 promoters, inducing re-expression. Inhibits invasor pehotype thus prevents metastasis | (163) | |
| Polyphenol | Chlorogenic acid | Natural Compound (not approved) | DNMT1 | Increases SAH formation inhibiting DNA methylation through COMT mechanism (non-competitive), | Breast Cancer cells | Inhibits DNMT1 activity, reduces methylation of the promoter region of the RARb gene | (150) |
| Harmine | Natural Compound (not approved) | DNMT1 | Not described | Myeloid Leukemia cells | Decreases DNMT1 gene expression, induces p15 promoter demethylation. Also decreases proliferation and promotes cell cycle arrest in G0/G1 phase | (149) | |
| Laccaic acid A (LCA) | Natural Compound (not approved) | DNMT1 | DNA-competitive DNMT inhibitor through competition for the oligonucleotide substrate | Breast Cancer cells | Inhibits directly DNMT1, also have effects on DNMT3A, 3B inhibition, and reactivates genes silenced by promoter methylation (CEACAM5, DHRS3, RGS16) | (151) | |
| Mahanine | Natural Compound (not approved) | DNMT1, DNMT3B | Induces proteasomal degradation of DNMT1 and DNMT3B | Prostate Cancer cells | Inhibits DNMT activity, increases expression of RASSF1A and inhibits cyclin D1. Induces proteosomal degradation on DNMT1 and DNMT3B through Akt inactivation, thus facilitates demethylation of RASSF1A promoter and increases its expression | (155, 171) | |
| Genistein | Natural compound; isoflavone | DNMT | Inhibits DNA methyltransferase activity in a substrate- and methyl donor–dependent manner | Esophageal Squamous Cell Carcinoma cells | Promotes reversed DNA hypermethylation and reactivation of RARbeta, p16INK4a and MGMT trhough demethylation of promoter genes. Also inhibites cell growth |
(172) | |
| Prostate Cancer cells | Induces DNA hypomethylation and reactivation of RARbeta | ||||||
| Breast Cancer cells | |||||||
| Renal Cancer cells | Inhibits DNMT1 activity, thus induces demethylation of BTG3 promoter and has antiproliferative effects through cell cycle arrest | (173) | |||||
| Peptide | Beta amiloid peptide | Component of Alzheimer’s senile plaque | DNMT | Drecreases SAM/SAHlevels, promoting a global demethylation, through redox-dependent control over methionine synthase and methylation |
Neuroblastoma cells | Soluble Aβ oligomers decreases intracellular glutathione levels by hampering cysteine uptake, followed by a global decrease in global DNA methylation | (174) |
| BCM7 | Natural Compound; food-derived peptide | DNMT | Decreases SAM/SAH levels, promoting decrease in cysteine levels, affecting redox status and methylation capacity of DNMTs | Neuroblastoma cells | Decreases cysteine absorption through opioid receptor activation. This reduction is followed by an increase of oxidized glutathione and an increase in DNA methylation | (175, 176) | |
| GM7 | Natural Compound; food-derived peptide | DNMT | Neuroblastoma cells | ||||
| Section 2. DNMT and HDAC Dual Inhibitors | |||||||
| Polyphenol | Parthenolide | Anti‐inflammatory (not approved) | HDAC1 and DNMT1 | Inhibits DNMT1possibly through alkylation of the proximal thiolate of Cys1226 of the catalytic domain by its -methylene lactone |
Colon Cancer cells | Inhibits HDAC activity by molecular docking, downregulates HIF-1alfa and inhibits NF-kB pathway | (177, 178) |
| Melanoma cells | Reduces MITF-M transcript level and HDAC1 and protein level. | (179) | |||||
| Breast Cancer cells | Induces proteasomal degradation of HDAC1, thus increasing global histone acetylation and p21/p53 expression and induces cell death. | (179–181) | |||||
| Thyroid Cancer cells | Down-regulates DNMT1 expression possibly associated with its SubG1 cell-cycle arrest. Promotes global DNA hypomethylation and reactivates HIN-1 gene trough demethylation of its promoter | (181) | |||||
| Myeloid Leukemia (AML) cells | Inhibits DNMT1 and decreases gene expression of DNMT1 and BF-kB pathway. Induces cell cycle arrest and interrupts the binding of Sp1 to DNMT1 promoter, thus reactivates tumor suppressor genes and inhibites HIF-α | (178, 181) | |||||
| Resveratrol (RVT/RSV) | Natural Compound polyphenol (not approved); | HDAC1 and DNMT | Fits into the binding pocket of HDAC’s though interaction with amino acids of the catalytic site and interacts with the zinc ion, disrupting HDAC-zinc dependent activity. | Hepatoblastoma cells | Antiproliferative effect on all cell lines; showed specific inhibition of HDACs and in turn a histone hyperacetylation in HepG2 cells. | (182) | |
| Breast Cancer cells | Decreases PRMT5 EZH2 ATP2A3 and HDAC2 expression, increasing H3ac and H3K27 marks; increases global level of H3K9ac and H3K27ac marks through increasing KAT2A/3B expression. Reduces the enrichment of H4R3me2s and H3K27me3; and increases activating histone marks (H3K9/27ac) within the proximal promoter region of BRCA1, p53, and p21 restoring its expression. | (183, 184) | |||||
| Thyroid Cancer cells | Decreases DNMT1 activity and demethylates CpG sites at promoters regions in CRABP2. | (185) | |||||
| EGCG | Natural Compound; thiol anti-inflammatory | DNMT and HDAC | Inhibitor of DNMT nuclear activity by direct interaction with a hydrophilic pocket of DNMT1 and catalytic binding site | Squamous Cell carcinoma cells | Induces reversal hypermethytlation in RARβ, MGMT, p16INK4a, and hMLH1 promoter genes, promotes inhibition of cell growth. | (186, 187) | |
| Skin Cancer cells | Increases the levels of acetylation of histone H3 and histone H4 lysine residues through HDAC inhibition, leading to the upregulation of Cip1/p21 and p16INK4a. | (188) | |||||