Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

Abstract

Introduction: Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy.

Area covered: Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated.

Expert opinion: While both transcriptional and post-translational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed.

Keywords: Cisplatin; Sp1; copper chelators; copper homeostasis; hCtr1; high-affinity copper transporter 1; platinum drug cancer chemotherapy.

Figure 1. The shared import and export mechanisms of Cu and platinum drugs

(A) hCtr1 transports Cu⁺¹ by endocytosis, (B) The Cu chaperone Atox1 captures Cu by interacting with hCtr1. Cu is then transferred to ATP7A/ATP7B for eliminating by secretory vesicles. (C) The Cu chaperone CCS captures Cu by interacting with hCtr1. (D) hCtr1 may directly transport Cu into the cells.

Figure 2. Schematics of Cu homeostasis regulation

(a) Cu depletion upregulates Sp1. (b) Upregulated Sp1 increases hCtr1 expression, (c) Increased hCtr1 enhances Cu transport. (d) Increased Cu suppresses hCtr1 expression. (e) Reduced Sp1 down-regulates hCtr1, resulting in reduced Cu (f).