Melatonin and (−)-Epigallocatechin-3-Gallate: Partners in Fighting Cancer

Abstract

We have demonstrated previously that melatonin attenuates hepatotoxicity triggered by high doses of (−)-epigallocatechin-3-gallate (EGCG) in mice. The current work investigated the influence of melatonin on the oncostatic activity of EGCG in two cancer cell lines, wherein melatonin induced an opposite response of p21. In human tongue cancer TCA8113 cells, melatonin-induced p21 and EGCG-mediated formation of quinoproteins were positively associated with the oncostatic effects of melatonin and EGCG. Melatonin-stimulated an increase in p21 which was correlated with a pronounced nuclear translocation of thioredoxin 1 and thioredoxin reductase 1, both of which are known to induce p21 via promoting p53 trans-activation. Melatonin did not influence the EGCG-mediated increase of quinoprotein formation nor did EGCG impair melatonin-induced p21 up-regulation. Co-treatment with both agents enhanced the cell-killing effect as well as the inhibitory activities against cell migration and colony formation. It is known that p21 also plays a powerful anti-apoptotic role in some cancer cells and confers these cells with a survival advantage, making it a target for therapeutic suppression. In human hepatocellular carcinoma HepG2 cells, melatonin suppressed p21 along with the induction of pro-survival proteins, PI3K and COX-2. However, EGCG prevented against melatonin-induced PI3K and COX-2, and melatonin probably sensitized HepG2 cells to EGCG cytotoxicity via down-regulating p21, Moreover, COX-2 and HO-1 were significantly reduced only by the co-treatment, and melatonin aided EGCG to achieve an increased inhibition on Bcl2 and NFκB. These events occurring in the co-treatment collectively resulted in an enhanced cytotoxicity. In addition, the co-treatment also enhanced the inhibitory activities against cell migration and colony formation. Overall, the results gathered from these two cancer cell lines with a divergent p21 response to melatonin show that the various oncostatic activities of melatonin and EGCG together are more robust than each agent alone, suggesting that they may be useful partners in fighting cancer.

Melatonin as an Antitumor Agent against Liver Cancer: An Updated Systematic Review

“…These results were validated using an in vivo model of xenograft tumor treated with 25 mg/kg body weight (daily for 18 days) [ 46 ]. More recently, a preliminary study using HepG2 HCC cells, has also confirmed that 3 mM melatonin increased the antiproliferative effects of (–)-epigallocatechin-3-gallate (EGCG) through a p21-associated mechanism [ 56 ].…”

“…In recent years, there has been an increasing interest on the use of flavonoids as anticancer agents [ 62 ]. In vitro experiments have also demonstrated that 2 and 4 mM melatonin co-administration potentiates the proapoptotic effects of EGCG in HepG2 cells by inhibition of Bcl-2 and COX-2, resulting in an enhanced cytotoxicity against HCC cells [ 56 ].…”

PTEN/AKT/mTOR signaling mediates anticancer effects of epigallocatechin‑3‑gallate in ovarian cancer

“…Exploring novel therapeutic drugs is essential for the treatment of ovarian cancer. EGCG has been demonstrated to possess anticancer bioactivity, which has attracted attention; EGCG has demonstrated cancer preventive activity in various types of human cancer, including lung, oral cavity and esophageal cancers (37,38). Numerous studies have been conducted on the effects of EGCG on lung cancer (39)(40)(41)(42), and it had been reported that oral administration of EGCG was feasible and safe to patients with advanced lung cancer (43).…”

Antioxidant and Pro-Oxidant Activities of Melatonin in the Presence of Copper and Polyphenols In Vitro and In Vivo

“…EGCG has shown many beneficial health effects; however, high-dose EGCG is apt to trigger hepatotoxicity [19,20]. We have previously demonstrated that melatonin ameliorated EGCG-induced hepatotoxicity in mice [42] and enhanced anticancer activities of EGCG in vitro [43]. We recently showed that EGCG and DEDTC, both at a safe dose, synergistically induced hepatotoxicity in mice because DEDTC-increased hepatic copper promoted EGCG oxidation [25].…”