(-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit tumorigenesis and cancer cell growth in animal models. Nevertheless, the dose-response relationship of the inhibitory activity in vivo has not been systematically characterized. The present studies were conducted to address these issues, as well as the involvement of reactive oxygen species (ROS), in the inhibitory action of EGCG in vivo and in vitro. We characterized the inhibitory actions of EGCG against human lung cancer H1299 cells in culture and in xenograft tumors. The growth of tumors was dose dependently inhibited by EGCG at doses of 0.1, 0.3 and 0.5% in the diet. Tumor cell apoptosis and oxidative DNA damage, assessed by the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and phosphorylated histone 2A variant X (gamma-H2AX), were dose dependently increased by EGCG treatment. However, the levels of 8-OHdG and gamma-H2AX were not changed by the EGCG treatment in host organs. In culture, the growth of viable H1299 cells was dose dependently reduced by EGCG; the estimated concentration that causes 50% inhibition (IC(50)) (20 microM) was much higher than the IC(50) (0.15 microM) observed in vivo. The action of EGCG was mostly abolished by the presence of superoxide dismutase (SOD) and catalase, which decompose the ROS formed in the culture medium. Treatment with EGCG also caused the generation of intracellular ROS and mitochondrial ROS. Although EGCG is generally considered to be an antioxidant, the present study demonstrates the pro-oxidative activities of EGCG in vivo and in vitro in the described experimental system.

Organotellurides are newly described redox-catalyst molecules with original pro-oxidative properties. We have investigated the in vitro and in vivo antitumoral effects of the organotelluride catalyst LAB027 in a mouse model of colon cancer and determined its profile of toxicity in vivo. LAB027 induced an overproduction of H 2 O 2 by both human HT29 and murine CT26 colon cancer cell lines in vitro. This oxidative stress was associated with a decrease in proliferation and survival rates of the two cell lines. LAB027 triggered a caspase-independent, ROS-mediated cell death by necrosis associated with mitochondrial damages and autophagy. LAB027 also synergized with the cytotoxic drug oxaliplatin to augment its cytostatic and cytotoxic effects on colon cancer cell lines but not on normal fibroblasts. The opposite effects of LAB027 on tumor and on non-transformed cells were linked to differences in the modulation of reduced glutathione metabolism between the two types of cells. In mice grafted with CT26 tumor cells, LAB027 alone decreased tumor growth compared with untreated mice, and synergized with oxaliplatin to further decrease tumor development compared with mice treated with oxaliplatin alone. LAB027 an organotelluride catalyst compound synergized with oxaliplatin to prevent both in vitro and in vivo colon cancer cell proliferation while decreasing the in vivo toxicity of oxaliplatin. No in vivo adverse effect of LAB027 was observed in this model. Cell Death and Disease (2011) 2, e191; doi:10.1038/cddis.2011.73; published online 11 August 2011Subject Category: Cancer All living organisms need to maintain a healthy intracellular redox balance in order to survive and to proliferate. 1 Reactive oxygen species (ROS) are natural by-products of aerobic metabolism whose production correlates with normal cell proliferation through the activation of growth-related signaling pathways. 2 Exposure to low levels of ROS can stimulate the growth of many types of mammalian cells, whereas scavengers of ROS suppress normal cell proliferation in human and rodent fibroblasts. 3,4 Furthermore, growth factors trigger the production of hydrogen peroxide (H 2 O 2 ) that leads to mitogenactivated protein kinase activation and DNA synthesis, a phenomenon inhibited by antioxidant molecules. 5,6 Several observations suggest that ROS also participate in carcinogenesis. First, ROS production is increased in cancer cells, and an oxidative stress can induce DNA damages that lead to genomic instability and possibly stimulate cancer progression. 7 Second, elevated ROS levels are responsible for the activation of transcription factors, such as NF-kB and AP-1 during tumor progression. 8 Several studies have shown that different types of cancer cells such as colon, liver, lung, kidney, prostate and skin cancer cells 9-11 display a high proliferation rate associated with an increased endogenous production of ROS and a downregulation of their antioxidant enzymatic systems.On the other hand, ROS can also induce the apoptosis/ necrosis of cancer cells....