title: Drug transporters play a key role in the complex process of Imatinib resistance in vitro.
abstract: Imatinib resistance has been associated with BCR-ABL alterations, but other mechanisms might be involved, like drug transporters. Additionally, the impact of poor adherence in resistance has been little explored. Using sensitive and resistance CML cell lines, we investigated the expression of influx/efflux transporters, like P-gP and OCT1. In the therapeutic interruption model, we observed decrease of influx and increase in efflux transporters combined with BCR-ABL over-expression. Comparatively, resistant cells obtained by continuous TKI exposure only demonstrated alterations in drug's transporters. By exploring P-gP expression of resistant cells, we observed the potential of P-gP inhibitor in circumventing Imatinib resistance. Our results revealed the importance of treatment interruptions for expected response levels and show the complexity of Imatinib resistant process. Efflux transports appear as not only relevant for acquisition of resistant phenotype, but also as valid therapeutic tool for managing resistance.
authors.affiliation: Applied Molecular Biology and University Clinic of Hematology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Portugal; CIMAGO - Center of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Alves
authors.affiliation: Applied Molecular Biology and University Clinic of Hematology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana Raquel
authors.initials: AR
authors.lastname: Fonseca
authors.affiliation: Applied Molecular Biology and University Clinic of Hematology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Portugal; CIMAGO - Center of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Gonçalves
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Ferreira-Teixeira
authors.affiliation: Clinical Pathology Service, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Lima
authors.affiliation: CIMAGO - Center of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Biophysics Unit, IBILI - Institute of Biomedical Research in Light and Image, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Abrantes
authors.affiliation: Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Vera
authors.initials: V
authors.lastname: Alves
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Portugal; CIMAGO - Center of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodrigues-Santos
authors.affiliation: Clinical Pathology Service, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal.
authors.forename: Lénia
authors.initials: L
authors.lastname: Jorge
authors.affiliation: Cytogenetic and Genomics Lab, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Eunice
authors.initials: E
authors.lastname: Matoso
authors.affiliation: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Portugal; CIMAGO - Center of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Cytogenetic and Genomics Lab, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Carreira
authors.affiliation: CIMAGO - Center of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Biophysics Unit, IBILI - Institute of Biomedical Research in Light and Image, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Maria Filomena
authors.initials: MF
authors.lastname: Botelho
authors.affiliation: Applied Molecular Biology and University Clinic of Hematology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Portugal; CIMAGO - Center of Investigation in Environment, Genetics and Oncobiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Portugal. Electronic address: absarmento@fmed.uc.pt.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sarmento-Ribeiro
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: CML; Imatinib resistance; Membrane drug transporters; OCT1; P-glycoprotein; Therapeutic interruptions