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Review

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

1
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2
Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
3
Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan
4
Center of Applied Nanomedicine, National Cheng Kung University, Tainan 701, Taiwan
*
Authors to whom correspondence should be addressed.
Academic Editor: Carlo Marchetti
Pharmaceuticals 2021, 14(6), 549; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060549
Received: 20 May 2021 / Revised: 5 June 2021 / Accepted: 7 June 2021 / Published: 8 June 2021
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs. View Full-Text
Keywords: cisplatin; carboplatin; oxaliplatin; copper transporter; Ctr1; Atox1; ATP7A. ATP7B. Sp1; copper chelator cisplatin; carboplatin; oxaliplatin; copper transporter; Ctr1; Atox1; ATP7A. ATP7B. Sp1; copper chelator
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MDPI and ACS Style

Kuo, M.T.; Huang, Y.-F.; Chou, C.-Y.; Chen, H.H.W. Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy. Pharmaceuticals 2021, 14, 549. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060549

AMA Style

Kuo MT, Huang Y-F, Chou C-Y, Chen HHW. Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy. Pharmaceuticals. 2021; 14(6):549. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060549

Chicago/Turabian Style

Kuo, Macus T., Yu-Fang Huang, Cheng-Yang Chou, and Helen H.W. Chen 2021. "Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy" Pharmaceuticals 14, no. 6: 549. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060549

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