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 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.

Cysteine-activated hydrogen sulfide (H2S) delivery through caged carbonyl sulfide (COS) donor motifs

“…Among these, thiol species, such as Cys and reduced glutathione (GSH), attract the most attention due to their cellular abundance and potent reactivity. Cys and GSH have been widely used to trigger biologically active molecules and prodrugs to release caged compounds, including sulfur dioxide (SO 2 ), 11 nitroxyl (HNO), 12 and anti-cancer drugs. 13 Importantly, thiol activation strategies have been adopted in H 2 S donor development and several thiol labile H 2 S donors exhibit promising protections in animal models with some of them currently in clinical trials.…”

[Ru(bpy)2(NO)SO3](PF6), a Nitric Oxide Donating Ruthenium Complex, Reduces Gout Arthritis in Mice

“…In vitro studies comparing NO release capacity demonstrated that Complex I is capable of releasing NO after reacting with thiols and presents superior physico-chemical properties and stability compared to other metal complexes ( Silva et al, 2006 , 2011 ). In addition to NO, the thiol reaction with metallonitrosyl complexes, such as Complex I, can generate HNO (nitroxyl) ( Silva Sousa et al, 2016 ). Nitroxyl donors have also analgesic, anti-inflammatory and microbicide actions ( Zarpelon et al, 2013 ; Staurengo-Ferrari et al, 2014b , 2017 ; Longhi-Balbinot et al, 2016 ).…”

Exploring Innovative Leishmaniasis Treatment: Drug Targets from Pre‐Clinical to Clinical Findings

“…evaluated the leishmanicidal potential of the ruthenium nitrosol complex (RuNO, S8) against L. brasiliensis by means of an in vitro (mice dermal fibroblasts) and an in vivo study (using hamsters) [41] . The nitrosyl ruthenium complexes have proven biological activity, such as antiparasitic, antiangiogenic, analgesic, gastroprotective and cerebral neuroprotection [44–49] . In this study, the authors showed that RuNo had no cytotoxic effect on dermal fibroblasts at any of the concentrations tested.…”