Over the course of the last several years, we have found that vairous redox related species such as nitric oxide play a major role in the promotion of angiogenesis as well as part of the inflammatory response. A recent study has shown that NO regulates a number of proteins such as TSP-1, TGF beta, metallo matrix proteases (MMP), TIMP, HIF-1alpha, Akt, ERK and p53. We have found a correlation been Akt and Nitric oxide synthase in breast cancer patients. We have begun to correlate our molecular studies in vitro with patient slides. These ahve begun to provide us insight into the role this small diatomic radical associated with oxidative stress plays in cancer. Another important aspect to this project is to see if we can develop compounds that can reverse the interactions of NO and the stimulation of these pro-growth effects. In animal models, we have found NOS inhibitors can induce a tumor re-growth delay after radiation thus improving the efficacy of these treatments. It was further found that it was the inflammatory response after treatment rather than simple its anti-angiogenic effect. We have been investigating the role of NO in the regulation of interferon gamma and IL-10. The final aspect of this project was the discovery with collaboration in the CCR, that the protein thrombospondin-1 (TSP-1, a antiangiogenic molecule) was the antagonist to NO/cGMP. Furthermore, we found nitric oxide antagonizes TSP-1. Removal of TSP-1 and its receptor CD47 improve normal tissue radiation induced damage and ischemia reperfusion injury. We are currently working on small molecules that can down regulate TSP-1 in vivo that improves blood flow.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Baseler, Walter A; Davies, Luke C; Quigley, Laura et al. (2016) Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production. Redox Biol 10:12-23
Ridnour, Lisa A; Cheng, Robert Y S; Weiss, Jonathan M et al. (2015) NOS Inhibition Modulates Immune Polarization and Improves Radiation-Induced Tumor Growth Delay. Cancer Res 75:2788-99
Miller, Thomas W; Soto-Pantoja, David R; Schwartz, Anthony L et al. (2015) CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation. J Biol Chem 290:24858-74
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
Soto-Pantoja, David R; Ridnour, Lisa A; Wink, David A et al. (2013) Blockade of CD47 increases survival of mice exposed to lethal total body irradiation. Sci Rep 3:1038
Schoenfeld, Michael P; Ansari, Rafat R; Nakao, Atsunori et al. (2012) A hypothesis on biological protection from space radiation through the use of new therapeutic gases as medical counter measures. Med Gas Res 2:8
Ridnour, Lisa A; Barasch, Kimberly M; Windhausen, Alisha N et al. (2012) Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation. PLoS One 7:e44081
Ridnour, Lisa A; Dhanapal, Sneha; Hoos, Michael et al. (2012) Nitric oxide-mediated regulation of ?-amyloid clearance via alterations of MMP-9/TIMP-1. J Neurochem 123:736-49
Soto-Pantoja, David R; Miller, Thomas W; Pendrak, Michael L et al. (2012) CD47 deficiency confers cell and tissue radioprotection by activation of autophagy. Autophagy 8:1628-42
Schoenfeld, Michael P; Ansari, Rafat R; Zakrajsek, June F et al. (2011) Hydrogen therapy may reduce the risks related to radiation-induced oxidative stress in space flight. Med Hypotheses 76:117-8

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