Silva Sousa, Eduardo Henrique, Ridnour, Lisa A., Gouveia, Florêncio S., Silva da Silva, Carlos Daniel, Wink, David A., de França Lopes, Luiz Gonzaga and Sadler, P. J. (2016) Thiol-Activated HNO release from a ruthenium antiangiogenesis complex and HIF-1α inhibition for cancer therapy. ACS Chemical Biology, 11 (7). pp. 2057-2065. doi:10.1021/acschembio.6b00222

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Abstract

Metallonitrosyl complexes are promising as nitric oxide (NO) donors for the treatment of cardiovascular, endothelial, and pathogenic diseases, as well as cancer. Recently, the reduced form of NO– (protonated as HNO, nitroxyl, azanone, isoelectronic with O2) has also emerged as a candidate for therapeutic applications including treatment of acute heart failure and alcoholism. Here, we show that HNO is a product of the reaction of the RuII complex [Ru(bpy)2(SO3)(NO)]+ (1) with glutathione or N-acetyl-L-cysteine, using met-myoglobin and carboxy-PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) as trapping agents. Characteristic absorption spectroscopic profiles for HNO reactions with met-myoglobin were obtained, as well as EPR evidence from carboxy-PTIO experiments. Importantly, the product HNO counteracted NO-induced as well as hypoxia-induced stabilization of the tumor-suppressor HIF-1α in cancer cells. The functional disruption of neovascularization by HNO produced by this metallonitrosyl complex was demonstrated in an in vitro angiogenesis model. This behavior is consistent with HNO biochemistry and contrasts with NO-mediated stabilization of HIF-1α. Together, these results demonstrate for the first time thiol-dependent production of HNO by a ruthenium complex and subsequent destabilization of HIF-1α. This work suggests that the complex warrants further investigation as a promising antiangiogenesis agent for the treatment of cancer.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Cancer -- Treatment, Nitric oxide
Journal or Publication Title:	ACS Chemical Biology
Publisher:	American Chemical Society
ISSN:	1554-8929
Official Date:	2016
Dates:	Date Event 2016 UNSPECIFIED
Date of first compliant deposit:	10 January 2017
Volume:	11
Number:	7
Page Range:	pp. 2057-2065
DOI:	10.1021/acschembio.6b00222
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Brazil. Coordenação do Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP), European Research Council (ERC), Engineering and Physical Sciences Research Council (EPSRC), National Institutes of Health (U.S.) (NIH)
Grant number:	303732/2014-8, 312030/2015-0 (CAPES) (CNPq), PPSUS 12535691-9 (FUNCAP), Grant no 247450 (ERC), Grant no. EP/F034210/1 (EPSRC)

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