Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy

• Published in: Expert opinion on therapeutic targets Vol. 19; no. 10; p. 1307
• Main Authors: Chen, Helen H W, Chen, Wen-Chung, Liang, Zhang-Dong, Tsai, Wen-Bin, Long, Yan, Aiba, Isamu, Fu, Siqing, Broaddus, Russell, Liu, Jinsong, Feun, Lynn G, Savaraj, Niramol, Kuo, Macus Tien
• Format: Journal Article
• Language: English
• Published: England 01.01.2015
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Biological Transport; Cation Transport Proteins - genetics; Chelating Agents - pharmacology; Copper - metabolism; Drug Resistance, Neoplasm; Humans; Neoplasms - drug therapy; Neoplasms - pathology; Platinum Compounds - administration & dosage; Up-Regulation - drug effects; hCtr1; high-affinity copper transporter 1; platinum drug cancer chemotherapy; Sp1; copper chelators; copper homeostasis; Cisplatin
• ISSN: 1744-7631
• DOI: 10.1517/14728222.2015.1043269

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. 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. 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.