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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.
Highlights
Melatonin is a potent antioxidant with an unequivocal oncostatic property [1,2,3,4,5,6]
In two cancer cell lines examined with diverged p21 response to melatonin, we consistently found that melatonin and EGCG together were more effective than each agent alone in suppressing cell growth, cell migration and colony formation
Because this concept was established using high concentration of melatonin which initiates pronounced cytotoxic response, we subsequently investigated the influence of a lower concentration of melatonin on p21 and nuclear Trx1/TrxR1
Summary
Melatonin is a potent antioxidant with an unequivocal oncostatic property [1,2,3,4,5,6]. Numerous studies have shown that melatonin acts as an antioxidant in normal cells or tissues under oxidative stress, via direct scavenging reactive oxygen species (ROS), inducing antioxidant enzymes or activating nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant defense system [3,7,8,9]. Cells 2019, 8, 745 aberrantly accumulated Nrf and overexpression of DJ1, thioredoxin (Trx) and thioredoxin reductase (TrxR) [10,11,12,13], melatonin no longer plays antioxidant roles but in turn becomes a prooxidant agent to heighten oxidant stress to cause cell death [4,5]. In the last three decades, an increasing body of evidence suggests that green tea catechins have health promotion effects, such as alleviation of metabolic syndrome and prevention of neurodegenerative diseases and cancer [27]
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