Epithelial NADPH oxidases are flavoproteins that catalyze the NADPH-dependent reduction of oxygen to superoxide following binding of ligands for receptor tyrosine kinases (including EGF, PDGF, VEGF). Current evidence suggests that NADPH-dependent reactive oxygen species play a critical role in growth factor-mediated signal transduction, and that the NADPH oxidase 1 isoform is abundantly expressed in human colon cancers. Because inhibition of constitutive oxidant production and cell growth of human colon cancer cell lines, as well as induction of apoptosis and blockade of the G1/S transition and induction of p27, occurred over the same concentration range for a series of iodonium-based flavoprotein inhibitors, Dr. Doroshows studies suggest that the therapeutic potential of iodonium NADPH oxidase inhibitors may be related to modification of redox-related signal transduction pathways essential for colorectal cancer cell growth. Iodonium derivatives have also been found to be active in two human colon cancer xenograft models. In future studies, Dr. Doroshow plans to develop additional, novel members of the iodonium drug class as potential therapeutic agents. Dr. Doroshow has also employed stable shRNA constructs developed in his laboratory (that are capable of downregulating NADPH oxidase 1 expression by >80%) to specifically investigate the role of this protein in colorectal cancer cell proliferation. These recent studies demonstrate that downregulation of NADPH Oxidase 1 leads to a significant decrease in reactive oxygen production in HT-29 cells, a G1 cell cycle block, down regulation of a large number of antiangiogenic genes, and inhibition of reactive oxygen-mediated signaling through several receptor protein kinases. In addition, we have found that the activity of several serine threonine and tyrosine phosphatases are increased when NADPH oxidase is knocked out. In vivo, downregulation of NADPH oxidase 1 dramatically decreases the growth of HT-29 xenografts, in part due to diminished angiogenesis. We have also found that pro-inflammatory cytokines involved in the pathogenesis of colon cancer strongly upregulate NADPH Oxidase 1. These studies strongly suggest that NADPH oxidase 1 is an important potential drug target in colon cancer.
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