Title
Interaction of Copper Trafficking Proteins with the Platinum Anticancer Drug Kiteplatin
Author
Alessandra Barbanente, Angela Galliani, Rosa Maria Lacobazzi, Alessia Lasorsa, Maria Incoronata Nardella, Antonio Pennetta, Nicola Margiotta, Fabio Arnesano
Year
2021
Journal
ChemMedChem
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.
Instrument
J-810
Keywords
interaction, metallodrugs, proteins, ATPase, structural properties