Abstract

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 criical to angiogenesis and that NO and TSP-1 regulate each other pathways. We have shown that the proangiogenic mechanisms of NO is abated by TSP-1 and that the transcription of the antiangiogenic agent TSP-1 was inhibited by NO. This seminal finding sheds light on the potential mechanism of the tumor re-growth delay by NOS inhibitors. We have also been examining the physiological effects of nitroxyl (HNO/NO-) a redox sibling of NO. We have found it to be valuable in the treatment of heart failure, precondition organs against ischemia reperfusion and a selective COX-2 inhibitor. We have recently developed new compounds that can be modified to deliver nitroxyl in vivo. In addition, we have established an HPLC method for specific detection of NO from chemical or biochemical sources.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC007281-12
Application #
7292044
Study Section
(RBB)
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2005
Total Cost
Indirect Cost

  Institution

Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Switzer, Christopher H; Flores-Santana, Wilmarie; Mancardi, Daniele et al. (2009) The emergence of nitroxyl (HNO) as a pharmacological agent. Biochim Biophys Acta 1787:835-40
Ridnour, Lisa A; Thomas, Douglas D; Switzer, Christopher et al. (2008) Molecular mechanisms for discrete nitric oxide levels in cancer. Nitric Oxide 19:73-6
Donzelli, Sonia; Espey, Michael Graham; Flores-Santana, Wilmarie et al. (2008) Generation of nitroxyl by heme protein-mediated peroxidation of hydroxylamine but not N-hydroxy-L-arginine. Free Radic Biol Med 45:578-84
Matsumoto, Shingo; Espey, Michael Graham; Utsumi, Hideo et al. (2008) Dynamic monitoring of localized tumor oxygenation changes using RF pulsed electron paramagnetic resonance in conscious mice. Magn Reson Med 59:619-25
Wink, David A; Paolocci, Nazareno (2008) Mother was right: eat your vegetables and do not spit! When oral nitrate helps with high blood pressure. Hypertension 51:617-9
Tocchetti, Carlo G; Wang, Wang; Froehlich, Jeffrey P et al. (2007) Nitroxyl improves cellular heart function by directly enhancing cardiac sarcoplasmic reticulum Ca2+ cycling. Circ Res 100:96-104
Isenberg, Jeff S; Jia, Yifeng; Fukuyama, Julia et al. (2007) Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake. J Biol Chem 282:15404-15
Prueitt, Robyn L; Boersma, Brenda J; Howe, Tiffany M et al. (2007) Inflammation and IGF-I activate the Akt pathway in breast cancer. Int J Cancer 120:796-805
Paolocci, Nazareno; Jackson, Matthew I; Lopez, Brenda E et al. (2007) The pharmacology of nitroxyl (HNO) and its therapeutic potential: not just the Janus face of NO. Pharmacol Ther 113:442-58
Isenberg, Jeff S; Hyodo, Fuminori; Matsumoto, Ken-Ichiro et al. (2007) Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation. Blood 109:1945-52

Showing the most recent 10 out of 34 publications