Since the discovery that nitric oxide (NO) is a physiologically relevant molecule, there has been great interest in the use of metal nitrosyl compounds as antitumor pharmaceuticals. Particularly interesting are those complexes which can deliver NO to biological targets. Ruthenium- and osmium-based compounds offer lower toxicity compared to other metals and show different mechanisms of action as well as different spectra of activity compared to platinum-based drugs. Novel ruthenium- and osmium-nitrosyl complexes with azole heterocycles were studied to elucidate their cytotoxicity and possible interactions with DNA. Apoptosis induction, changes of mitochondrial transmembrane potential and possible formation of reactive oxygen species were investigated as indicators of NO-mediated damage by flow cytometry. Results suggest that ruthenium- and osmium-nitrosyl complexes with the general formula (indazolium)[cis/trans-MCl4(NO)(1H-indazole)] have pronounced cytotoxic potency in cancer cell lines. Especially the more potent ruthenium complexes strongly induce apoptosis associated with depolarization of mitochondrial membranes, and elevated reactive oxygen species levels. Furthermore, a slight yet not unequivocal trend to accumulation of intracellular cyclic guanosine monophosphate attributable to NO-mediated effects was observed.
Bibliographical noteKAUST Repository Item: Exported on 2020-10-01
Acknowledgements: Austrian Science Fund (FWF). We are deeply
grateful to Prof. Dr. Vladimir Arion for overall support and collaborations.
Authors wish to thank Anatolie Gavriluta (Université Claude
Bernard Lyon 1, France) for cooperation. This work was performed as
part of an Austrian-French joint project supported in France by ANR
(Agence Nationale de la Recherche) through the project VILYGRu
(No. ANR-09-BLAN-0420-01) and in Austria by the Austrian Science
Fund (FWF) through the project I374-N19. Partial support by
the Austrian Science Fund through the project P-22339-N19 is also