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 found that HNO, a one electron derivative of NO, has unique vascular effects as well as potentiating glutamate receptor function. These effects have led to development of new methods to treat heart failure. In our previous studies, we were able to show that nitrosative chemistry can dramatically increase the efficacy of some chemotherapeutic agents through the inhibition of DNA repair proteins such as PARP. Growth factor receptors IGFR and EGFR, but not VEGFR, are also negatively affected by nitrosation. We have also shown that unique redox signatures of p53 and HIF-1 are produced from specific NO redox chemistry. The analytical methods for the study of NO and related reactive nitrogen oxide species in cells and tissue are complex. We have developed a series of sensitive techniques to monitor intracellular reactive nitrogen oxide chemistry. This will provide a valuable probe in designing new transfected cells as well as new drugs that can specifically target NO chemistry to the tumor.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC007281-10
Application #
6947586
Study Section
(RBB)
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2003
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