Abstract
Platinum drugs are widely used for cancer treatment. Other precious metals are promising, but their clinical progress depends on achieving different mechanisms of action to overcome Pt-resistance. Here, we evaluate 13 organo-Os complexes: 16-electron sulfonyl-diamine catalysts [(η6-arene)Os(N,N′)], and 18-electron phenylazopyridine complexes [(η6-arene)Os(N,N’)Cl/I]+ (arene = p-cymene, biphenyl, or terphenyl). Their antiproliferative activity does not depend on p21 or p53 status, unlike cisplatin, and their selective potency toward cancer cells involves the generation of reactive oxygen species. Evidence of such a mechanism of action has been found both in vitro and in vivo. This work appears to provide the first study of osmium complexes in the zebrafish model, which has been shown to closely model toxicity in humans. A fluorescent osmium complex, derived from a lead compound, was employed to confirm internalization of the complex, visualize in vivo distribution, and confirm colocalization with reactive oxygen species generated in zebrafish.
Highlights
Cancer is one of the leading causes of death in the developed world.[1,2] As many as half of all cancer chemotherapy regimens include a platinum drug, which typically targets DNA, and is either administered alone or in combination therapies.[3]both intrinsic and acquired Pt-resistances are major clinical concerns,[4−6] requiring the development of drugs that circumvent this problem by possessing an alternative or multitargeted mechanism of action (MoA).Other precious metals have promising anticancer activity, including organo-Os
Antiproliferative activities (IC50 values, concentrations that inhibit 50% of cell growth) toward nine human cell lines were determined for complexes 1−13 by investigating cell viability after drug exposure (24 h + 72 h recovery time) using the SRB assay, and compared to the anticancer drug, cisplatin
In the cell lines investigated in this study, the osmium complexes exhibited highest potency against A2780 ovarian cancer cells, achieving nanomolar potency, compared to lower potency of previously reported Ru(II) analogues (IC50 2−6 μM, depending on azopyridine ligand and η6-arene).[54]
Summary
Cancer is one of the leading causes of death in the developed world.[1,2] As many as half of all cancer chemotherapy regimens include a platinum drug, which typically targets DNA, and is either administered alone or in combination therapies.[3] Both intrinsic and acquired Pt-resistances are major clinical concerns,[4−6] requiring the development of drugs that circumvent this problem by possessing an alternative or multitargeted mechanism of action (MoA). We investigate the translation of the mechanism of action and accumulation of Os(II) arene complexes from in vitro cellular studies to a readily available in vivo model
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