Table 2. Reversal of cancer metabolism using epigenetic drugs.
| Inhibitor | Target enzyme | Mode of Action | Ongoing clinical use/trials | Ref |
|---|---|---|---|---|
| DNMT inhibitors | ||||
| 5-Azacytidine, 5-Aza-2'-deoxycytidine | DNA methyltransferases | Both drugs non-selectively inactivate DNMT1, DNMT3A and DNMT3B DNMT inhibitors reversed the hypermethylator phenotype in IDH1-mutant glioma cells | Azacitidine and 5-Aza-2′-deoxycytidine (Approved for myelodysplastic syndrome and acute myeloid leukemia, Phase I-III for other malignancies) | 198, 199 |
| HDAC inhibitors | ||||
| Butyrate, Romidepsin, Trichostatin A, Valproic acid, Vorinostat | Histone deacetylases (HDACs) | HDAC inhibitors induce histone acetylation and reverse aberrant gene expression caused by HDACs. Treatment of cancer cells with HDAC inhibitors was associated with the reduction in glucose uptake, glycolytic flux and lactate metabolism | Romidepsin and Vorinostat (Approved for cutaneous T cell lymphoma, Phase I-III for other malignancies), Valproic acid (Phase I-III) | 200, 201, 202, 203 |
| Sirtuin activators and inhibitors | ||||
| Linoleic acid, Myristic acid, Oleic acid | Sirtuin 6 (SIRT6) | Free fatty acids activate SIRT6, which functions as a tumor suppressor to inhibit glycolysis | NA | 204 |
| miRNA modulators | ||||
| Synthetic miRNA mimics | miRNAs | miRNA mimics restores silenced miRNA function. For example, re-expression of miR-143, which targets hexokinase II 3′-UTR, suppressed glycolysis | NA | 154 |
| miRNA sponges, Antisense oligonucleotides | miRNAs | Anti-miRs silences overexpressed miRNA. For example, anti-miR-21 restored PTEN expression | NA | 209 |
Abbreviations: HDAC, histone deacetylase; miRNA, microRNA; NA, not applicable; 3′-UTR, 3′-untranslated region.