title: Thiol-Activated HNO Release from a Ruthenium Antiangiogenesis Complex and HIF-1α Inhibition for Cancer Therapy.
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.
authors.affiliation: Laboratory of Bioinorganic Chemistry, Department of Organic and Inorganic Chemistry, Federal University of Ceará , Mister Hull Avenue, Building 935, Fortaleza, Brazil 60455-760.|Department of Chemistry, University of Warwick , Coventry CV4 7AL, United Kingdom.
authors.forename: Eduardo Henrique
authors.initials: EH
authors.lastname: Silva Sousa
authors.affiliation: National Cancer Institute , Cancer and Inflammation Program, Frederick, Maryland 21702, United States.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Ridnour
authors.affiliation: Laboratory of Bioinorganic Chemistry, Department of Organic and Inorganic Chemistry, Federal University of Ceará , Mister Hull Avenue, Building 935, Fortaleza, Brazil 60455-760.
authors.forename: Florêncio S
authors.initials: FS
authors.lastname: Gouveia
authors.affiliation: Laboratory of Bioinorganic Chemistry, Department of Organic and Inorganic Chemistry, Federal University of Ceará , Mister Hull Avenue, Building 935, Fortaleza, Brazil 60455-760.|Department of Chemistry, Federal Institute of Bahia , Salvador, 40301-150, Brazil.
authors.forename: Carlos Daniel
authors.initials: CD
authors.lastname: Silva da Silva
authors.affiliation: National Cancer Institute , Cancer and Inflammation Program, Frederick, Maryland 21702, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Wink
authors.affiliation: Laboratory of Bioinorganic Chemistry, Department of Organic and Inorganic Chemistry, Federal University of Ceará , Mister Hull Avenue, Building 935, Fortaleza, Brazil 60455-760.
authors.forename: Luiz Gonzaga
authors.initials: LG
authors.lastname: de França Lopes
authors.affiliation: Department of Chemistry, University of Warwick , Coventry CV4 7AL, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy*; D009569:Nitric Oxide / Q000737:chemistry; D009589:Nitrogen Oxides / Q000737:chemistry*; D012428:Ruthenium / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009589:Nitrogen Oxides; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D012428:Ruthenium; C039900:nitroxyl