We have been developing strategies to utilize nitric oxide (NO) in cancer treatment. In addition to the use of synthetic NO donors, we are researching the mechanisms that control the endogenous cellular production. We have recently discovered that inhibition of Nitric oxide synthase (NOS) given after chemotherapy or radiation treatment enhances tumor re-growth delay. Given that there are a number of clinically available NOS inhibitors this could have potential clinical applications. We have recently characterized the NO levels that are required to activate and stabilize key proteins involved in carcinogenesis, p53, ERK and HIF. We have extended this work to show that levels of NO are critical to angiogenesis and that NO and TSP-1 regulate each other pathways. Our extension of the understanding of angiogenic responses and nitric oxide has lead us to understand the regulation of Matrix Metalloproteases (MMP) by NO . Our findings suggest that under inflammatory response MMP are regulated by two different mechanisms, biologocal signlaing and direct chemical modification. The first is via TIMP through cGMP. The second are through chemical reactivity of RNS. We demonstrated that MMP9 secreted from macrophage was a critical facotr in the NO mediated wound healing response. Another important area of reseach is our investigation of nitroxyl (HNO) which has been shown to have some unique properties from its redox cousin nitric oxide. Though NO was discovered in the 1980s and many of the higher oxides of nitrogen have been studied, the reduced nitrogen oxide such as HNO have just recently begun to be examined. This small molecule has been shown to have promising effects in the preconditioning against myocardiac infarction and improve contractility under heart failure conditions. We have also found that HNO can regulate the activity of P450, COX-2 and TGFbeta implicating a possible role in cancer. One of the major questions concerning its biology is whether HNO is an intermediate generated in vivo. We have developed methods to determine if HNO can be generated from different biochemical mechanism involving proteins and other molecules can interact with other biological targets. One of the largest discovery in this project is that HNO donors may be an effective treatment for heart failure as well as preconditioning the coronary against ischemia reperfusion injury or heart attacks. This projects future goal is to determine mechanism of endogenous generation of HNO as well as find different pharmacological properties that may be useful in cancer treatment as well as heart disease. .

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC007281-17
Application #
8158273
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2010
Total Cost
$369,445
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
de Oliveira, Graciele Almeida; Cheng, Robert Y S; Ridnour, Lisa A et al. (2017) Inducible Nitric Oxide Synthase in the Carcinogenesis of Gastrointestinal Cancers. Antioxid Redox Signal 26:1059-1077
Cortese-Krott, Miriam M; Koning, Anne; Kuhnle, Gunter G C et al. (2017) The Reactive Species Interactome: Evolutionary Emergence, Biological Significance, and Opportunities for Redox Metabolomics and Personalized Medicine. Antioxid Redox Signal 27:684-712
Kovacevic, Z; Sahni, S; Lok, H et al. (2017) Regulation and control of nitric oxide (NO) in macrophages: Protecting the ""professional killer cell"" from its own cytotoxic arsenal via MRP1 and GSTP1. Biochim Biophys Acta 1861:995-999
Basudhar, Debashree; Ridnour, Lisa A; Cheng, Robert et al. (2016) Biological signaling by small inorganic molecules. Coord Chem Rev 306:708-723
Thomas, Douglas D; Heinecke, Julie L; Ridnour, Lisa A et al. (2015) Signaling and stress: The redox landscape in NOS2 biology. Free Radic Biol Med 87:204-25
Heinrich, Tassiele A; da Silva, Roberto S; Miranda, Katrina M et al. (2013) Biological nitric oxide signalling: chemistry and terminology. Br J Pharmacol 169:1417-29
Ridnour, Lisa A; Cheng, Robert Y S; Switzer, Christopher H et al. (2013) Molecular pathways: toll-like receptors in the tumor microenvironment--poor prognosis or new therapeutic opportunity. Clin Cancer Res 19:1340-6
Switzer, Christopher H; Glynn, Sharon A; Cheng, Robert Y-S et al. (2012) S-nitrosylation of EGFR and Src activates an oncogenic signaling network in human basal-like breast cancer. Mol Cancer Res 10:1203-15
Switzer, Christopher H; Ridnour, Lisa A; Cheng, Robert et al. (2012) S-Nitrosation Mediates Multiple Pathways That Lead to Tumor Progression in Estrogen Receptor-Negative Breast Cancer. For Immunopathol Dis Therap 3:117-124
Switzer, Christopher H; Cheng, Robert Y-S; Ridnour, Lisa A et al. (2012) Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer. Breast Cancer Res 14:R125

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