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.
Highlights
Cisplatin [cis-diamminedichloroPt(II)] (Figure 1) is an important chemotherapeutic drug used in the therapy of a broad spectrum of human malignancies such as ovarian, testicular, head and neck, and lung cancers, and in combination with a wide range of other drugs for the treatment of other malignancies
According to the Human Genome Organisation (HUGO), human transporters are classified based on their amino acid sequence in 43 solute carrier (SLC) families [23]; Cu transporters have been assigned to the SLC31A family
KP1019 was tested against a panel of chemosensitive cell lines and their chemoresistant sublines expressing defined resistance mechanisms; the results showed that the cytotoxic effects of KP1019 are not substantially hampered by overexpression of the drug resistance proteins multidrug resistance-related protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) or the transferrin receptor, and only marginally by the cellular p53 status
Summary
Cisplatin [cis-diamminedichloroPt(II)] (Figure 1) is an important chemotherapeutic drug used in the therapy of a broad spectrum of human malignancies such as ovarian, testicular, head and neck, and lung cancers, and in combination with a wide range of other drugs for the treatment of other malignancies. Due to its higher water solubility, NKP-1339 has been selected as a lead candidate for further clinical development Besides these coordination compounds, several classes of other metal complexes and organometallic compounds, based on different metals such as Au, Fe, Ag, Ga, Rh, and Ti, exhibit promising anticancer activity at least in preclinical studies [4,5,6,7,8]. Clinical pharmacokinetic drug-drug interaction (DDI) studies have suggested that transporters often work together with drug-metabolizing enzymes (DMEs) in drug absorption and elimination In spite of their great importance, transport mechanisms of anticancer metallodrugs have not yet been fully elucidated, especially in the case of a new generation of cytotoxic metal complexes. The use of bioactive ligands to enhance the cellular uptake of metal compounds will be presented
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