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. These studies strongly suggest that NADPH oxidase 1 is an important potential drug target in colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010677-09
Application #
8763174
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2013
Total Cost
$530,788
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Roy, Krishnendu; Wu, Yongzhong; Meitzler, Jennifer L et al. (2015) NADPH oxidases and cancer. Clin Sci (Lond) 128:863-75
Hayes, Patti; Dhillon, Sandeep; O'Neill, Kim et al. (2015) Defects in NADPH Oxidase Genes NOX1 and DUOX2 in Very Early Onset Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol 1:489-502
Esworthy, Robert S; Kim, Byung-Wook; Chow, Joni et al. (2014) Nox1 causes ileocolitis in mice deficient in glutathione peroxidase-1 and -2. Free Radic Biol Med 68:315-25
Meitzler, Jennifer L; Antony, Smitha; Wu, Yongzhong et al. (2014) NADPH oxidases: a perspective on reactive oxygen species production in tumor biology. Antioxid Redox Signal 20:2873-89
Doroshow, James H; Gaur, Shikha; Markel, Susan et al. (2013) Effects of iodonium-class flavin dehydrogenase inhibitors on growth, reactive oxygen production, cell cycle progression, NADPH oxidase 1 levels, and gene expression in human colon cancer cells and xenografts. Free Radic Biol Med 57:162-75
Esworthy, R Steven; Kim, Byung-Wook; Wang, Yufeng et al. (2013) The Gdac1 locus modifies spontaneous and Salmonella-induced colitis in mice deficient in either Gpx2 or Gpx1 gene. Free Radic Biol Med 65:1273-83
Doroshow, James H; Juhasz, Agnes; Ge, Yun et al. (2012) Antiproliferative mechanisms of action of the flavin dehydrogenase inhibitors diphenylene iodonium and di-2-thienyliodonium based on molecular profiling of the NCI-60 human tumor cell panel. Biochem Pharmacol 83:1195-207