title: Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a 1 National Cheng Kung University, National Cheng Kung University Hospital, College of Medicine, Department of Radiation Oncology , Tainan, Taiwan.
authors.forename: Helen H W
authors.initials: HH
authors.lastname: Chen
authors.affiliation: b 2 National Cheng Kung University, National Cheng Kung University Hospital, College of Medicine, Department of Pathology , Tainan, Taiwan.
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Chen
authors.affiliation: c 3 The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology , Houston, TX 77030, USA.
authors.forename: Zhang-Dong
authors.initials: ZD
authors.lastname: Liang
authors.affiliation: c 3 The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology , Houston, TX 77030, USA.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Tsai
authors.affiliation: d 4 The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology , Houston, TX 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: e 5 The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology , Houston, TX 77030, USA.
authors.forename: Isamu
authors.initials: I
authors.lastname: Aiba
authors.affiliation: f 6 The University of Texas MD Anderson Cancer Center, Departments of Investigative Cancer Therapeutics , Houston, TX, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: g 7 The University of Texas MD Anderson Cancer Center, Departments of Pathology , Houston, TX, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Broaddus
authors.affiliation: g 7 The University of Texas MD Anderson Cancer Center, Departments of Pathology , Houston, TX, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: h 8 University of Miami, Sylvester Comprehensive Cancer Center , 1475 NW 12th Avenue, Miami, FL 33136, USA.
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Feun
authors.affiliation: h 8 University of Miami, Sylvester Comprehensive Cancer Center , 1475 NW 12th Avenue, Miami, FL 33136, USA.
authors.forename: Niramol
authors.initials: N
authors.lastname: Savaraj
authors.affiliation: i 9 The University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology , Unit 2951, LSP 9.4206, 2130 W. Holcombe Blvd, Houston, TX 77030, USA +1 713 834 6038 ; +1 713 834 6085 ; tkuo@mdanderson.org.
authors.forename: Macus Tien
authors.initials: MT
authors.lastname: Kuo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000235:genetics*; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D000079923:Copper Transporter 1; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017671:Platinum Compounds / Q000008:administration & dosage; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D027682:Cation Transport Proteins; D002614:Chelating Agents; D000079923:Copper Transporter 1; D017671:Platinum Compounds; C490079:SLC31A1 protein, human; D003300:Copper
keywords: Cisplatin; Sp1; copper chelators; copper homeostasis; hCtr1; high-affinity copper transporter 1; platinum drug cancer chemotherapy