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 #
1ZIABC010677-07
Application #
8349099
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2011
Total Cost
$445,918
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Meitzler, Jennifer L; Makhlouf, Hala R; Antony, Smitha et al. (2017) Decoding NADPH oxidase 4 expression in human tumors. Redox Biol 13:182-195
Juhasz, Agnes; Markel, Susan; Gaur, Shikha et al. (2017) NADPH oxidase 1 supports proliferation of colon cancer cells by modulating reactive oxygen species-dependent signal transduction. J Biol Chem 292:7866-7887
Chu, Fong-Fong; Esworthy, R Steven; Doroshow, James H et al. (2017) Deficiency in Duox2 activity alleviates ileitis in GPx1- and GPx2-knockout mice without affecting apoptosis incidence in the crypt epithelium. Redox Biol 11:144-156
Lu, Jiamo; Risbood, Prabhakar; Kane Jr, Charles T et al. (2017) Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases. Biochem Pharmacol 143:25-38
Antony, Smitha; Jiang, Guojian; Wu, Yongzhong et al. (2017) NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates normoxic HIF-1? and p27Kip1 expression in malignant melanoma and other human tumors. Mol Carcinog 56:2643-2662
Liu, Han; Antony, Smitha; Roy, Krishnendu et al. (2017) Interleukin-4 and interleukin-13 increase NADPH oxidase 1-related proliferation of human colon cancer cells. Oncotarget 8:38113-38135
Wu, Yongzhong; Meitzler, Jennifer L; Antony, Smitha et al. (2016) Dual oxidase 2 and pancreatic adenocarcinoma: IFN-?-mediated dual oxidase 2 overexpression results in H2O2-induced, ERK-associated up-regulation of HIF-1? and VEGF-A. Oncotarget 7:68412-68433
Chu, Fong-Fong; Esworthy, R Steven; Doroshow, James H et al. (2016) NADPH oxidase-1 deficiency offers little protection in Salmonella typhimurium-induced typhlitis in mice. World J Gastroenterol 22:10158-10165
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

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