Abstract
Recent studies suggest that of the molecules postulated to function as inhibitors of the NADPH oxidase family of enzymes iodonium analogs known to broadly interfere with flavin dehydrogenase function demonstrate mechanistic validity as NADPH oxidase poisons. In recent work, we have produced a series of novel iodonium compounds as putative inhibitors of these oxidases. To evaluate the potential utility of two novel molecules with favorable chemical properties, NSC 740104 and NSC 751140, we compared effects of these compounds to the two standard inhibitors of this class, diphenyleneiodonium and di-2-thienyliodonium, with respect to antiproliferative, cell cycle, and gene expression effects in human colon cancer cells that require the function of NADPH oxidase 1. Both new agents blocked NADPH oxidase-related reactive oxygen production, inhibited tumor cell proliferation, produced a G1/S block in cell cycle progression, and inhibited NADPH oxidase 1 expression at the mRNA and protein levels at low nM concentrations in a fashion similar to or better than the parent molecules. These studies suggest that NSC 740104 and NSC 751140 should be developed further as mechanistic tools to better understand the role of NADPH oxidase inhibition as an approach to the development of novel therapeutic agents for colon cancer.
Highlights
The seven members of the NADPH oxidase (NOX) family, NADPH oxidase 1 (NOX1)-5 and dual oxidases (DUOX) 1 and 2, are essential transmembrane enzymes that are widely expressed across normal and malignant tissues [1]
We found that HT-29 cells in which NOX1 expression was inhibited by shRNA demonstrated a profound decrease in reactive oxygen species (ROS) production as well as a significant decrease in proliferation both when cultured in vitro and when propagated as xenografts carried by athymic mice
Because the goal of these studies was to examine the effects of a series of iodonium analogs on NOX1, we evaluated the baseline expression of each component of the NOX1 complex in three different human colon cancer cell lines
Summary
The seven members of the NADPH oxidase (NOX) family, NOX1-5 and dual oxidases (DUOX) 1 and 2, are essential transmembrane enzymes that are widely expressed across normal and malignant tissues [1]. (NOX4 and DUOX1 and 2), these proteins play a critical role in the maintenance of host defense, the initiation of an inflammatory response, cytokine signaling, angiogenesis, vascular tone, and cellular proliferation [2,3,4,5,6]. There is accumulating evidence that pre-malignant conditions (including inflammatory bowel disease and pancreatitis) [7,8] that occur as a consequence of chronic, unrestrained inflammation may, at least in part, be mediated by NOX family oxidase-dependent production of reactive oxygen species (ROS) [9]. NOX1 is most abundantly expressed by epithelial cells found in both the small and large intestine [10].
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