TABLE 4.
Reversal of epigenetic dysfunction by targeting metabolism.
| Target pathway | Metabolic enzyme | Pharmacological agents | Mechanism | Indications | References |
|---|---|---|---|---|---|
| Glycolysis | Hexokinases | 2-DG (phase-I/II) | 2-DG suppresses hexokinase that is a rate-limiting enzyme for glycolysis; 2-DG reduces acetyl-CoA level, which inhibits the acetylation of histones in various cancer cell lines | lung cancer, breast cancer, pancreatic cancer, prostate cancer, lymphoma | Chen and Guéron, (1992); Liu et al. (2015) |
| Glutaminolysis | Glutaminase (GLS) | CB-839 (phase-I); Compound-968; Zaprinast | GLS inhibitors reduce acetyl-CoA and 2-HG level; Compound-968 decreases histone H3K4me3 in breast cancer and Zaprinast reduces H3K9me3 in IDH1-mutant cancer cells | AML, ALL, MM, NHL, pancreatic carcinoma | Robinson et al. (2007); Wang et al. (2010a); Simpson et al. (2012a); Simpson et al. (2012b); Elhammali et al. (2014) |
| Serine/glycine metabolism | PHGDH | shRNA to PHGDH | Inhibiting the process of de novo serine synthesis | NA | Locasale et al. (2011); Possemato et al. (2011) |
| One-carbon cycle | SAH hydrolase | DZNep; Adenosine Dialdehyde | Both agents could increase the SAH/SAM ratio and decrease DNA and histone methylation | NA | Jiang et al. (2008); Miranda et al. (2009); Momparler et al. (2012); Schäfer and Balleyguier, (2013); Momparler and Côté, (2015) |
| IDH1 inhibitor | IDH1-mutant | AG-120, IDH305, AG-881, BAY1436032, FT-2102, AGI-5198, GSK-321 | IDH1 inhibitors suppress the production of 2-HG that is a kind of oncometabolite in IDH1-mutant cells; AGI-5198 prompts demethylation of H3K9me3 and H3K27me3 in IDH1-mutant chondrosarcoma cells; GSK-321 induces DNA hypomethylation in IDH1-mutant AML cells | AML, solid tumors, gliomas, hematologic malignancies | Rohle et al. (2013); Zheng et al. (2013a); Davis et al. (2014); Deng et al. (2015); Kim et al. (2015); Li et al. (2015); Okoye-Okafor et al. (2015) |
| IDH2 inhibitor | IDH2-mutant | AG-221, AG-881, AGI-6780 | IDH2 inhibitors suppress the production of 2-HG that is a kind of oncometabolite in IDH2-mutant cells; AG-221 and AGI-6780 prompt demethylation of DNA and histone in IDH2-mutant cancer cells | AML, solid tumors, gliomas, hematologic malignancies | Wang et al. (2013); Kernytsky et al. (2015) |
| NNMT inhibitor | N-Methylnicotinamide | Nicotinamide N-methyltransferase (NNMT) | NNMT inhibitors reduce SAM level and histone methylation in NNMT-overexpressed cells | NA | Kraus et al. (2014) |
2-DG, 2-Deoxyglucose; GLS, glutaminase; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; MM, multiple myeloma; NHL, Non-Hodgkin Lymphoma; NA, not applicable.