Cellular Transport Mechanisms of Cytotoxic Metallodrugs: An Overview beyond Cisplatin

Abstract

Abstract:The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.

Coordination compounds in cancer: Past, present and perspectives

“…Both of them show antitumor activity, but Ru(III) is probably in vivo first reduced to Ru(II) acting rather as a prodrug. This reduction process seems to be more effective in hypoxic tumour tissues, lacking normal oxygen partial pressure (Clarke et al, 1999;Clarke, 2002;Spreckelmeyer et al, 2014). The reduction process, Ru(III) !…”

Potent organo-osmium compound shifts metabolism in epithelial ovarian cancer cells

“…With the move toward personalized medicine, it becomes vital to elucidate the MOA for new metal-based drugs so that treatments can be matched to the predicted response of particular cancer cells. Hence, we adopted a systems biology approach to gain insight into the activity of compound 1 (33).…”

Ferrocenyl‐Coupled N‐Heterocyclic Carbene Complexes of Gold(I): A Successful Approach to Multinuclear Anticancer Drugs

“…[45][46][47][48] Both complexes 8 and 10 are delocalized lipophilic cations (DLC), whichare known to accumulate in mitochondria, disturb the essential functions of these, and lead to the loss of Dy m , eventually inducing the intrinsic pathway of apoptosis. [52] Antivascular effects Both complexes initiated ac oncentration-dependent reduction in the fraction of cells with an intact Dy m .D espite its less pronounced TrxR inhibition, the biscarbene complex 10,w hen applied at 1 mm,r educed the fraction of cells with unaltered Dy m to approximately 45 %, and thus more strongly than complex 8,w hich left approximately 65 %o fm itochondria with intact Dy m .Apossible explanationl ies in the higher lipophilicity of complex 10,w hich facilitates its uptake into mitochondria.…”