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Thiol-Activated HNO Release from a Ruthenium Antiangiogenesis Complex and HIF-1α Inhibition for Cancer Therapy.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2016 Jul 15; Vol. 11 (7), pp. 2057-65. Date of Electronic Publication: 2016 May 31. - Publication Year :
- 2016
-
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 Ru(II) 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.
- Subjects :
- Antineoplastic Agents therapeutic use
Cell Hypoxia
Cell Line, Tumor
Humans
Nitric Oxide chemistry
Angiogenesis Inhibitors chemistry
Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
Neoplasms drug therapy
Nitrogen Oxides chemistry
Ruthenium chemistry
Sulfhydryl Compounds chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 11
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 27191177
- Full Text :
- https://doi.org/10.1021/acschembio.6b00222