title: ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastases.
abstract: Overcoming drug resistance has become an important issue in cancer chemotherapy. Among all known mechanisms that confer resistance, active efflux of chemotherapeutic agents by proteins from the ATP-binding cassette family has been extensively reported. The aim of the present study was to determine the involvement of ABCG2 in resistance to SN38 (the active metabolite of irinotecan) in colorectal cancer. By progressive exposure to increasing concentrations of SN38, we isolated 2 resistant clones from the human colon carcinoma cell line HCT116. These clones were 6- and 53-fold more resistant to SN38 than the HCT116-derived sensitive clone. Topoisomerase I expression was unchanged in our resistant variants. The highest resistance level correlated with an ABCG2 amplification. This overexpression was associated with a marked decrease in the intracellular accumulation of SN38. The inhibition of ABCG2 function by Ko143 demonstrated that enhanced drug efflux from resistant cells was mediated by the activity of ABCG2 protein and confirmed that ABCG2 is directly involved in acquired resistance to SN38. Furthermore, we show, for the first time in clinical samples, that the ABCG2 mRNA content in hepatic metastases is higher after an irinotecan-based chemotherapy than in irinotecan-naive metastases. In conclusion, this study supports the potential involvement of ABCG2 in the development of irinotecan resistance in vivo.
authors.affiliation: CNRS-UMR 5160, Centre de Recherche en Cancérologie, CRLC Val d'Aurelle, Montpellier, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Candeil
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gourdier
authors.forename: Delphine
authors.initials: D
authors.lastname: Peyron
authors.forename: Nadia
authors.initials: N
authors.lastname: Vezzio
authors.forename: Virginie
authors.initials: V
authors.lastname: Copois
authors.forename: Frederic
authors.initials: F
authors.lastname: Bibeau
authors.forename: Beatrice
authors.initials: B
authors.lastname: Orsetti
authors.forename: George L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: Marc
authors.initials: M
authors.lastname: Ychou
authors.forename: Qasim A
authors.initials: QA
authors.lastname: Khan
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Bernard
authors.initials: B
authors.lastname: Pau
authors.forename: Pierre
authors.initials: P
authors.lastname: Martineau
authors.forename: Maguy
authors.initials: M
authors.lastname: Del Rio
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077146:Irinotecan; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C106003:SN38-Glu; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin