Biochemical Changes in Carcinogen Resistant Cells

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The primary focus of our study is to investigate the biochemical and molecular changes associated with carcinogen resistance toward cancer prevention. We developed a series of carcinogen-resistant cells by continuous exposure to benzo[a]pyrene (BP). These cells are a model for studying the early biochemical and molecular changes which may prevent cancer due to environmental carcinogens and xenobiotics. Our BP resistant cells are also co-resistant to DMBA, a mammary carcinogen in rodents. To our knowledge this is the first systematic examination of the overall mechanisms involved in carcinogen resistance, including carcinogen efflux, activation, and detoxification. Although certain detoxification enzymes, glutathione-s-transferase, glutathione peroxidase and glutathione reductase were unchanged, a significant increase in reduced glutathione levels was observed in BP resistant cells. Our observation suggested a redox mediated pathway cascade may be involved in carcinogen resistance. Therefore, we examined the major pathway enzyme of the pentose phosphate shunt, glucose-6-phosphate dehydrogenase (G6PD) activity. We found G6PD activities were markedly increased in BP resistant cells compared to WT. We proposed that one of the major changes in carcinogen resistant cells is in redox mediated mechanisms. Our hypothesis was further supported by molecular studies of protein and RNA expressions. The expressions of G6PD were increased with increasing resistance in human breast cancer cells. We further examined the G6PD regulation by dietary chemoprevention agents in human hepatoma cells and we found G6PD activity was enhanced by resveratrol and dibenzoylmethane. Our results suggested that the mechanism of action of certain chemoprevention agents may mediated by the redox cycle enzyme G6PD. Whether the redox changes are important in preventing carcinogen initiation in mammary or liver tumors are under our current investigation.