title: Collateral sensitivity to cisplatin in KB-8-5-11 drug-resistant cancer cells.
abstract: BACKGROUND
  KB-8-5-11 cells are a drug-resistant cervical cell model that overexpresses ABCB1 (P-glycoprotein). KB-8-5-11 has become sensitive to non-ABCB1 substrate cisplatin. Understanding the mechanism of collateral sensitivity to cisplatin may lead to biomarker discovery for platinum sensitivity in patients with cancer.
  
  
  METHODS
  A Taqman low-density array was used to characterize the expression of 380 genes previously associated with chemoresistance. Identified pathways were further analyzed using cytotoxicity assays, metabolomics and western blots.
  
  
  RESULTS
  KB-8-5-11 cells were sensitive to CuSO4 and the glutathione inhibitor buthionine sulphoximine. Expression of ATPase, Cu(2+) transporting alpha (ATP7A) and ATP7B were decreased at the protein and gene levels respectively in KB-8-5-11. KB-8-5-11 had decreased gene expression of glutathione S-transferase pi 1 (GSTP1), GSTA4 and GSTK1. Cisplatin treatment significantly lowered total cellular glutathione in parental KB-3-1 cells. Glutathione also tended to be lower in KB-8-5-11 cells compared to KB-3-1 cells.
  
  
  CONCLUSIONS
  KB-8-5-11 cells have alterations in their copper transporters and glutathione metabolism, contributing to their cisplatin-sensitive phenotype.
authors.affiliation: Department of Histopathology, Trinity College Dublin, 1.18 Sir Patrick Dun Research Laboratory, Central Pathology Building, St James' Hospital, Dublin 8, Ireland. stordalb@tcd.ie.
authors.forename: Ben
authors.initials: B
authors.lastname: Doherty
authors.forename: Denise
authors.initials: D
authors.lastname: Lawlor
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Gillet
authors.forename: Michael
authors.initials: M
authors.lastname: Gottesman
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Leary
authors.forename: Britta
authors.initials: B
authors.lastname: Stordal
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D000073840:Copper-Transporting ATPases; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055432:Metabolomics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D012333:RNA, Messenger; C487896:GSTK1 protein, human; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D000251:Adenosine Triphosphatases; C041116:leukotriene-C4 synthase; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases; D005978:Glutathione; D002945:Cisplatin
keywords: Cisplatin; KB-8-5-11 cells; cervical cancer; collateral sensitivity; drug resistance; paclitaxel