The inhibitory activity of gallic acid against DNA methylation: application of gallic acid on epigenetic therapy of human cancers

Abstract

Epigenome aberrations have been observed in tobacco-associated human malignancies. (−)-epigallocatechin-3-gallate (EGCG) has been proven to modulate gene expression by targeting DNA methyltransferases (DNMTs) through a proposed mechanism involving the gallate moiety of EGCG. We show that gallic acid (GA) changes the methylome of lung cancer and pre-malignant oral cell lines and markedly reduces both nuclear and cytoplasmic DNMT1 and DNMT3B within 1 week. GA exhibits stronger cytotoxicity against the lung cancer cell line H1299 than EGCG. We found that GA reactivates the growth arrest and DNA damage-inducible 45 (GADD45) signaling pathway may through the demethylation of CCNE2 and CCNB1 in H1299 cells. To improve the epigenetic anti-cancer activities of oolong tea, we identified a fungus, Aspergillus sojae which can efficiently increase the GA content in oolong tea via a 2-week fermentation process. The fungus dramatically increased GA up to 44.8 fold in the post-fermentation oolong tea extract (PFOTE), resulting in enhanced demethylation effects and a significant reduction in the nuclear abundances of DNMT1, DNMT3A, and DNMT3B in lung cancer cell lines. PFOTE also showed stronger anti-proliferation activities than oolong tea extract (OTE) and increased sensitivity to cisplatin in H1299 cells. In summary, we demonstrate the potent inhibitory effects of GA on the activities of DNMTs and provide a strong scientific foundation for the use of specialized fermented oolong tea high in GA as an effective dietary intervention strategy for tobacco-associated cancers.

Therapeutic Potential of Plant Phenolic Acids in the Treatment of Cancer

“…In addition, epigenome-protecting abilities of GA were also observed in tobacco-associated cancers. GA reduced nuclear and cytoplasmatic DNA methyltransferases in H1299 cells [37]. GA was also found to be a potent inhibitor of HDAC8 and class IIa/b HDAC activity [38].In addition, GA demonstrated anti-invasive effects in human nasopharyngeal carcinoma cells NPC-BM1 through the inhibition of p38 MAPK signaling pathway, this was due to suppressed transcription of MMP-1 by down-regulation of Ets1 and c-Jun, c-fos of the AP-1 [39].…”

“…In therapeutics a post-fermentation oolong tea extract (PFOTE) GA-enriched using Aspergillus sojae was associated with further enhanced demethylation abilities. PFOTE also increased sensitivity to cisplatin and showed stronger antiproliferative abilities when compared with oolong tea extract [37]. Furthermore, an ability of GA to potentiate side effects of conventional chemotherapeutic drugs was evaluated in HeLa cervical cancer cells.…”

Ameliorative effect of gallic acid in paclitaxel-induced neuropathic pain in mice

“…GA is a primary anti-oxidant component of tea extract. Ayurvedic herbs have large quantities of GA [26,30,31]. Experimentally, GA has been documented to produce anti-hyperlipidemic, cardioprotective, anti-diabetic activity [32,33].…”

The study of drug resistance properties of ABCG2 (ATP-binding cassette G2) in contact with thymoquinone, gallic acid, and hesperetin antioxidants

“…However, at much lower concentrations, the drug can play its role in the treatment process in cancer cells. Many studies have shown that GA is a powerful antioxidant compound in the death of cancer cells (43,44). Based on the results in Figure 2 and Table 1, GA interacts with amino acids in binding site by ten hydrogen bonds and six hydrophobic bonds.…”