![]() Unlike melatonin, EGCG at the dose levels that exhibit a solid anti-cancer, anti-obesity or anti-inflammation effects may evoke toxic reactions in certain normal tissues, particular in the liver. On the other hand, at high doses and in certain environments, EGCG can act as a prooxidant owing to its auto-oxidation, resulting in the formation of the superoxide anion and hydrogen peroxide. Like melatonin, EGCG is also an antioxidant via its direct quenching of ROS or indirect induction of basal and/or Nrf2-dependent antioxidant defense systems. In at least 13 animal models for human carcinogenesis of the lung, oral cavity, esophagus, stomach, small intestine, colorectal, colon, skin, liver, pancreas, bladder, prostate, or mammary glands, EGCG has shown cancer preventive activities. Since (−)-epigallocatechin-3-gallate (EGCG) accounts for over half of the catechins in green tea and is the most redox-active tea catechin due to its two ortho-dihydroxy structure, this naturally occurring compound has been used commercially as a dietary supplement. 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. ![]() Green tea, made from the plant Camellia sinensis L., has been consumed in China for over 4000 years and is currently one of the most popular beverages worldwide. The cell-context dependent feature of melatonin and its uncommonly high safety profile make melatonin a unique molecule for cancer prevention, or cancer adjunctive therapy for attenuating toxic reactions caused by chemotherapy or radiotherapy and sensitizing cancer cells to the therapy. Unlike many recognized antioxidant agents with prooxidant properties, such as selenium, with demonstrated adverse effects at doses required for achieving solid anti-cancer effects, melatonin is an exceptional antioxidant with prooxidant activity without documented serious adverse effects. However, in cancer cells with higher levels of ROS and concomitant expanded antioxidant arsenal such as aberrantly accumulated Nrf2 and overexpression of DJ1, thioredoxin (Trx) and thioredoxin reductase (TrxR), melatonin no longer plays antioxidant roles but in turn becomes a prooxidant agent to heighten oxidant stress to cause cell death. 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. Melatonin is a potent antioxidant with an unequivocal oncostatic property. 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. In addition, the co-treatment also enhanced the inhibitory activities against cell migration and colony formation. ![]() These events occurring in the co-treatment collectively resulted in an enhanced cytotoxicity. 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. In human hepatocellular carcinoma HepG2 cells, melatonin suppressed p21 along with the induction of pro-survival proteins, PI3K and COX-2. 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. Co-treatment with both agents enhanced the cell-killing effect as well as the inhibitory activities against cell migration and colony formation. Melatonin did not influence the EGCG-mediated increase of quinoprotein formation nor did EGCG impair melatonin-induced p21 up-regulation. 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. 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. 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. We have demonstrated previously that melatonin attenuates hepatotoxicity triggered by high doses of (−)-epigallocatechin-3-gallate (EGCG) in mice.
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