The Combination Of EGCC And Selenium Or Disulfiram On Anti-cancer Effect And EGCG-dispering Selenium Nanoparticles

(-)-Epigallocatechin-3-gallate(EGCG) is the major catechin component of green tea. EGCG has many benefits for huaman health, such as regulating glucolipid metabolism to prevent obesity, diabetes, cardiovascular and cancer. Due to many effects of EGCG was occurring at approached toxic dose, the current research mainly is focusing on the combination of EGCG and other nutrients or drugs and using nanotechnology to prepare the nanoparticles of EGCG or the nanoparticles of other materials prepared by EGCG as nanoparticles agent for enhancing the effect of EGCG on preventing diseases.The anti-cancer effect of EGCG on the proliferation of murine H22 hepatocarcinoma cells(H22 cells) in mice ascitic fluid was investigated. We found that no proliferation suppression effect of EGCG was observed; and whereas proliferation suppression effect of sodium selenite was dose-dependent with nutritious dose of selenium. Because of the higher levels of SOD activities in H22 cells, the auto-oxidation of EGCG in H22 cells were inactivated, so that the EGCG was lost the effect of inhibition of cancer cells proliferation. However, the GR and GSH were involved in the metabolism of selenium, forming into superoxide anion, which can be catalyzed by the higher levels of SOD activities forming into hydrogen peroxide. But the lower CAT and GPx activities cannot eliminate the cytotoxicity of hydrogen peroxide in time, leading to cancer cells apoptosis. Moreover, selenium was mainly concentrated in cancer cells when compared to selenium retention in normal tissues, showing at least an order of magnitude difference between the drug target cells and the well-recognized toxic target of selenium. Such a favorable selective distribution resulted in strong proliferation suppression without perceived host toxicity. The co-administration of EGCG and sodium selenite in mice ascetic fluid, moreover, revealed that there is no effect of EGCG on sodium selenite-induced proliferation suppression. Provided EGCG is further being demonstrated to be a future chemopreventive agent, its defect in coping with certain types of resistant cancer cells may be supplemented by selenium at a safe dose because the present study revealed EGCG-resistant H22 cells are sensitive to sodium selenite, imply selenium-enriched tea may have more comprehensive chemopreventive functions.EGCG-dispersed selenium nanoparticles was prepared using EGCG as dispersing agent, was characterized, and was evaluated bioavailability. The current results show that EGCG, in the form of phenolic anions at alkaline environment, can effectively disperse selenium nanoparticles. However, at acidic environment, the EGCG-dispersed selenium nanoparticles extensively aggregated so that nano features largely disappeared. This demonstrates that deprotonated phenolic anions of EGCG play an important role in maintaining EGCG-dispersed selenium nanoparticles stability and suggests that EGCG-dispersed selenium nanoparticles would suffer from reduced oral bioavailability. Although the oral bioavailability of EGCG-dispersed selenium nanoparticles was reduced, but the bioavailability of EGCG-dispersed selenium nanoparticles was well maintained via intraperitoneally injected, therefore EGCG-dispersed selenium nanoparticles as intraperitoneal chemotherapy agents can be used to prevent the proliferation of cancer cells in the abdominal cavity.The biological activity of combination of EGCG and diethyldithiocarbamate(DEDTC) or its oxidized form, disulfiram(DSF), was investigated. We found that co-administration of EGCG at the safely dose and DEDTC induced lethal toxicity in mice, leading to death and the serious liver damage, which significantly increased serum ALT and AST, two liver function biomarkers. The potential mechanism is that DEDTC, as a copper-chelating agent, can inhibit SOD vitality and increase the accumulation of copper in liver, exacerbating the auto-oxidation of EGCG in vivo formed into a large amount of superoxide anion and hydrogen peroxide, leading to increasing severe oxidative stress and the toxicity of EGCG. And, elevating GST or GSH related genes induced DEDTC, Nrf2 related genes, and antioxidant enzymes related genes in the liver were significantly inhibitedresulting into decreasing hepatic antioxidant level and two-phase of detoxification enzymes ability, leading to enhanced hepatic toxicity and extensive lethality.In conclusion, EGCG is recognized as a safe and natural anti-cancer agent, but EGCG cannot inhibit the proliferation of cancer cells in the abdominal cavity. Although the dose of selenium to prevent cancer is usually close the dose of selenium with toxicity, selenium can inhibit the proliferation of cancer cells in the abdominal cavity with nutritious dose of selenium, indicating that selenium can be used as abdominal cancer preventive agent. Therefore, the combination of EGCG and selenium can enhance the inhibition of proliferation of cancer cells in the abdominal cavity. We found that EGCG via the drug-delivery way of intraperitoneal injection has no impact on the effect of selenium, suggesting that the compatibility of between EGCG and selenium can expand the anti-cancer spectrum of EGCG. EGCG-dispersing selenium nanoparticles could partly lose its oral bioavailability, but the subject of selenium via intraperitoneal injection, indicating that the novel selenium nanoparticles can prevent the proliferation of cancer cells in the abdominal cavity. In addition, the increasing toxicity was found after the combination of EGCG and DEDTC, leading to lethality in mice. Therefore, the combination of between EGCG and other nutrients or drugs not only expect enhancing biological effects, but also should pay more attention to the potential risk.