(-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit cancer cell growth and tumorigenesis in animal models. As a possible mechanism of action, EGCG may bind to protein targets and directly or indirectly block signaling pathways essential for tumorigenesis or cancer cell growth. This study deals with a second type of action of EGCG involving the generation of reactive oxygen species (ROS), which induces cellular damage and apoptosis. This type of action can be easily demonstrated in human lung cancer H1299 cells; the induction of apoptosis by 25uM and 50uM of EGCG in serum-free medium was blocked by the addition of superoxide dismutase (SOD) plus catalase, which quenched the ROS formed in culture medium. The action of SOD/catalase was further enhanced by N-acetyl-cysteine. The production of ROS by EGCG in this experimental system and the decrease of ROS levels by SOD/catalase were demonstrated by dichlorofluorescin (DCF) staining. The oxidative DNA damage induced by EGCG was reflected in the formation of \#947;-H2AX, and \#947;-H2AX levels were decreased by SOD/catalase. Similar effects were also observed in human lung cancer H460 cells and mouse lung cancer CL-13 cells. The growth of H1299 xenograft tumors in NCR nu/nu mice was inhibited by about 70% as a result of daily i.p. injections of 40 mg/kg EGCG for 7 weeks. \#947;-H2AX levels were significantly increased in tumors of the treatment group compared to those of control. In the host mouse liver, levels of \#947;-H2AX and metallothionein were also increased indicative of oxidative stress. However, such an effect was not observed in the kidney. EGCG administration through the diet (0.2%) or in the drinking fluid (0.32%) did not induce \#947;-H2AX in the liver, even though 0.2% dietary treatment increased \#947;-H2AX in the xenograft tumor. It appears that the pro-oxidative activity is more pronounced in the xenograft tumor than in host tissues, but oxidative stress is induced when high concentrations of EGCG reach the liver. Although EGCG is generally considered to be an antioxidant, the present study demonstrates the pro-oxidative activities of EGCG in vitro and in vivo. Whether the pro-oxidative mechanism is involved in the cancer preventive activity of EGCG in a carcinogenesis model remains to be investigated (Supported by NIH grants CA120915, CA122474, and CA133021).

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2373.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009