Platinum transfer from hCTR1 to Atox1 is dependent on the type of platinum complex

Abstract

In spite of their wide application, the cellular uptake of platinum based anticancer drugs is still unclear. The copper transport protein, hCTR1, is proposed to facilitate the cellular uptake of cisplatin, whereas organic cation transport (OCT) is more important for oxaliplatin. It has been reported that both N-terminal and C-terminal metal binding motifs of hCTR1 are highly reactive to cisplatin, which is the initial step of protein assisted cellular uptake of cisplatin. It is still unknown how the platinum drugs in hCTR1 transfer to cytoplasmic media, and whether various platinum complexes possess different activities in this process. Herein, we investigated the reaction of the platinated C-terminal metal binding motif of hCTR1 (C8) with the down-stream protein Atox1. Results show that Atox1 is highly reactive to the platinated C8 adducts of cisplatin and transplatin, whereas the oxaliplatin/C8 adduct is much less reactive. The platinum transfer from C8 to Atox1 occurs in the reaction, which results in the protein unfolding of Atox1. These results demonstrated that the platinated intracellular-domain of hCTR1 is reactive to Atox1, and the reactivity is dependent on the ligand and the coordination structure of platinum complexes. The different reactivity is consistent with the hypothesis that hCTR1 is more significant in the transport of cisplatin than that of oxaliplatin.

The Multifaceted Roles of Copper in Cancer: a Trace Metal Element with Dysregulated Metabolism, but also a Target or a Bullet for Therapy

“…As a consequence, the drug's ability to penetrate cells decreases [74]. This is due to the fact that Cu binding sites are also used by platinum to enter cells via Ctr1 [75], but also for intracellular trafficking bound to Atox1 [76,77]. Moreover, therapeutic platinum salts can also be excreted outside cells by the Cu transporters ATP7A or ATP7B [78,79] .…”

Studying the cellular distribution of highly phototoxic platinated metalloporphyrins using isotope labelling

“…The transplatin moiety helps to improve solubility and transport of the PS into the cell while being non-toxic after cleavage of the conjugate. Transplatin is known to undergo faster efflux from the cell than cisplatin 19 . We also investigated the differences between the dark cytotoxcities of the trans-platinum series of compounds, tPt-H24PyP, tPt-Zn4PyP and tPt-Cu4PyP and the cis-platinum series, cPt-H24PyP, cPt-Zn4PyP and cPt-Cu4PyP.…”

Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy

“…Atox1 is a soluble protein of 68 amino acids, which captures Cu(I) by directly interacting with the C-terminal 188 HCH end of hCtr1. Atox1 coordinates one Cu(I) ion with the cysteine (Cys15) residues of the conserved 12 CXX 15 C motif in Atox1 dimerization [30][31][32].…”