Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs.
Recent studies have demonstrated that the major Cu influx transporter CTR1 regulates tumor cell uptake of cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (L-OHP), and that the two Cu efflux transporters ATP7A and ATP7B regulate the efflux of these drugs. Evidence for the concept that these platinum (Pt) drugs enter cells and are distributed to various subcellular compartments via transporters that have evolved to manage Cu homeostasis includes the demonstration of: (1) bidirectional cross-resistance between cells selected for resistance to either the Pt drugs or Cu; (2) parallel changes in the transport of Pt and Cu drugs in resistant cells; (3) altered cytotoxic sensitivity and Pt drug accumulation in cells transfected with Cu transporters; and (4) altered expression of Cu transporters in Pt drug-resistant tumors. Appreciation of the role of the Cu transporters in the development of resistance to DDP, CBDCA, and L-OHP offers novel insights into strategies for preventing or reversing resistance to this very important family of anticancer drugs.
Safaei
Roohangiz
R
Department of Medicine and the Rebecca and John Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0058, USA. rsafaei@ucsd.edu
Howell
Stephen B
SB
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000378:metabolism / Q000502:physiology*; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D019008:Drug Resistance, Neoplasm; D006801:Humans; D017671:Platinum Compounds / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D017671:Platinum Compounds; D011993:Recombinant Fusion Proteins; C490079:SLC31A1 protein, human; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases