Interaction of Copper Trafficking Proteins with the Platinum Anticancer Drug Kiteplatin

Abstract

The interaction of metallodrugs with proteins influences their mechanism of action and side effects. In the case of platinum drugs, copper transporters modulate sensitivity and resistance to these anticancer agents. To deepen the knowledge of the structural properties underlying the reactivity of platinum drugs with copper transporters, we studied the interaction of kiteplatin and two of its derivatives with the methionine-rich motif of copper importer Ctr1 and with the dithiol motif of the first domain of Menkes ATPase. Furthermore, cellular uptake and cytotoxicity of the three complexes were evaluated in cisplatin-sensitive and -resistant ovarian cancer cells, comparing the data with those of clinically relevant drugs. Reactivity depends on the tightness of the chelate ring formed by the carrier ligands and the nature of the leaving and entering groups. The results highlight the importance of subtle changes in the platinum coordination sphere that affect drug absorption and intracellular fate.

Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration

“…Kiteplatin, cis-1,4-diaminocyclohexane(dichlorido)platinum(II) or [PtCl2(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxalilplatin diamine ligand trans-1R,2R-diaminocyclohexane (1R,2R-DACH) and has been widely investigated as a potential new platinum anticancer drug (Figure 1). In particular, the interest in this compound stems from its activity against both cisplatin (ovarian C13) and oxaliplatin (colon LoVo-OXP)-resistant cancer cell lines [16][17][18][19]. Another strategy to overcome some limitations of conventional Pt(II) anticancer drugs, consists of the synthesis of the corresponding platinum(IV) derivatives to be used as prodrugs [4,[20][21][22][23][24].…”