Activation of carboplatin and nedaplatin by the N-terminus of human copper transporter 1 (hCTR1)

Abstract

Human copper transporter 1 (hCTR1) is a major copper uptake protein. Interestingly, it also mediates the uptake of selected platinum (Pt) anticancer drugs such as cisplatin and carboplatin. Here we studied the interactions of the N-terminus of hCTR1 (hCTR1-N) with carboplatin and its analogue nedaplatin by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Our 2D [ 1H, 15N] SOFAST-HMQC NMR data demonstrated that hCTR1-N binds to these Pt drugs through methionine residues to form ring-opened monofunctional adducts. Such a binding significantly activated these platinum drugs. High resolution ESI-MS spectra showed that a maximum of two Pt atoms bound per monomer of the protein for carboplatin and nedaplatin in a similar manner to cisplatin. In contrast, transplatin interacted with hCTR1-N more rapidly, yielding a different binding species with a maximum of five transplatin bound per monomer of the protein. The nucleophiles in serum, e.g. chloride and bicarbonate, can also play a role in the pre-activation of carboplatin and nedaplatin in the blood plasma prior to reaching their cellular targets. This study provides an insight into the possible mechanism of in vivo activation of Pt anticancer compounds with bidentate ligands. © 2012 The Royal Society of Chemistry.