Abstract

The chemical biology of HNO, is to determine the pharmacological and possible endogenous production of this species in vivo. One of the challenges is to determine the role that HNO may have in the biochemistry of nitric oxide synthase (NOS). In addition, we have found that NH2OH may be an important precursor to HNO under oxidative conditions. This indicates that hydroxyamic acids such as chemotherapeutic drugs hydroxyurea and SAHA may mediate some effects through HNO. Here we have investigated a variety of HNO donors and method of generation in vivo. We have currently discover a specific marker for HNO and found that it can be detected in cells. Furthermore, we have been able to determine protemic and genomic signature that differ from HNO and NO. These finding further support our hypothesis that these species have mutaully exclusive biology. We have current extended this project to better understand nitrosation and H2S as well as persulfides. In cancer, we have found that HNO will target tumor producing cell lines but not primary endothelial cells or non-tumorigenic cell lines. While in vivo these compounds are well tolerated being 20 times safer than aspirin, there is a profound selectivity in xenograph models. We are currently inviestigating what determines this selectivity. Furthermore we are trying to determine if these drugs can modify conventional therapy through synergisim.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011190-09
Application #
9556486
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Gao, Wei Dong; Murray, Christopher I; Tian, Ye et al. (2012) Nitroxyl-mediated disulfide bond formation between cardiac myofilament cysteines enhances contractile function. Circ Res 111:1002-11
Fukuto, Jon M; Carrington, Samantha J; Tantillo, Dean J et al. (2012) Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species. Chem Res Toxicol 25:769-93
Flores-Santana, Wilmarie; Salmon, Debra J; Donzelli, Sonia et al. (2011) The specificity of nitroxyl chemistry is unique among nitrogen oxides in biological systems. Antioxid Redox Signal 14:1659-74
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
Tocchetti, Carlo G; Stanley, Brian A; Murray, Christopher I et al. (2011) Playing with cardiac ""redox switches"": the ""HNO way"" to modulate cardiac function. Antioxid Redox Signal 14:1687-98
Andrei, Daniela; Salmon, Debra J; Donzelli, Sonia et al. (2010) Dual mechanisms of HNO generation by a nitroxyl prodrug of the diazeniumdiolate (NONOate) class. J Am Chem Soc 132:16526-32
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
Paolocci, Nazareno; Wink, David A (2009) The shy Angeli and his elusive creature: the HNO route to vasodilation. Am J Physiol Heart Circ Physiol 296:H1217-20
Samuni, Yuval; Flores-Santana, Wilmarie; Krishna, Murali C et al. (2009) The inhibitors of histone deacetylase suberoylanilide hydroxamate and trichostatin A release nitric oxide upon oxidation. Free Radic Biol Med 47:419-23
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

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