Thiol-Activated HNO Release from a Ruthenium Antiangiogenesis Complex and HIF-1α Inhibition for Cancer Therapy

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 therap...

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Bibliographic Details
Published in:ACS chemical biology 2016-07, Vol.11 (7), p.2057-2065
Main Authors: Silva Sousa, Eduardo Henrique, Ridnour, Lisa A, Gouveia, Florêncio S, Silva da Silva, Carlos Daniel, Wink, David A, de França Lopes, Luiz Gonzaga, Sadler, Peter J
Format: Article
Language:English
Subjects:
Angiogenesis Inhibitors - chemistry
Antineoplastic Agents - therapeutic use
Cell Hypoxia
Cell Line, Tumor
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
Neoplasms - drug therapy
Nitric Oxide - chemistry
Nitrogen Oxides - chemistry
Ruthenium - chemistry
Sulfhydryl Compounds - chemistry
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Summary: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.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.6b00222