Drug transporters play a key role in the complex process of Imatinib resistance in vitro

Raquel Alves; Ana Raquel Fonseca; Ana C Gonçalves; Margarida Ferreira-Teixeira; Joana Lima; Ana M Abrantes; Vera Alves; Paulo Rodrigues-Santos; Lénia Jorge; Eunice Matoso; Isabel M Carreira; Maria Filomena Botelho; Ana B Sarmento-Ribeiro

doi:10.1016/j.leukres.2014.12.008

Drug transporters play a key role in the complex process of Imatinib resistance in vitro

Leuk Res. 2015 Mar;39(3):355-60. doi: 10.1016/j.leukres.2014.12.008. Epub 2014 Dec 23.

Affiliations

¹ 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.
² Applied Molecular Biology and University Clinic of Hematology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
³ Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Portugal.
⁴ Clinical Pathology Service, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal.
⁵ 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.
⁶ Immunology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁷ 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.
⁸ Cytogenetic and Genomics Lab, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
⁹ 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.
¹⁰ 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.

PMID: 25575688
DOI: 10.1016/j.leukres.2014.12.008

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.

Keywords: CML; Imatinib resistance; Membrane drug transporters; OCT1; P-glycoprotein; Therapeutic interruptions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Apoptosis / drug effects
Benzamides / pharmacology*
Cell Proliferation / drug effects
Drug Resistance, Neoplasm*
Flow Cytometry
Fusion Proteins, bcr-abl / genetics
Humans
Imatinib Mesylate
In Situ Hybridization, Fluorescence
In Vitro Techniques
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
Organic Cation Transporter 1 / metabolism*
Piperazines / pharmacology*
Protein Kinase Inhibitors / pharmacology
Pyrimidines / pharmacology*
Tumor Cells, Cultured

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Benzamides
Organic Cation Transporter 1
Piperazines
Protein Kinase Inhibitors
Pyrimidines
Imatinib Mesylate
Fusion Proteins, bcr-abl