title: Impact of ABCB1 1236C > T-2677G > T-3435C > T polymorphisms on the anti-proliferative activity of imatinib, nilotinib, dasatinib and ponatinib.
abstract: Overexpression of ABCB1 (also called P-glycoprotein) confers resistance to multiple anticancer drugs, including tyrosine kinase inhibitors (TKIs). Several ABCB1 single nucleotide polymorphisms affect the transporter activity. The most common ABCB1 variants are 1236C > T, 2677G > T, 3435C > T and have been associated with clinical response to imatinib in chronic myelogenous leukaemia (CML) in some studies. We evaluated the impact of these polymorphisms on the anti-proliferative effect and the intracellular accumulation of TKIs (imatinib, nilotinib, dasatinib and ponatinib) in transfected HEK293 and K562 cells. ABCB1 overexpression increased the resistance of cells to doxorubicin, vinblastine and TKIs. Imatinib anti-proliferative effect and accumulation were decreased to a larger extent in cells expressing the ABCB1 wild-type protein compared with the 1236T-2677T-3435T variant relatively to control cells. By contrast, ABCB1 polymorphisms influenced the activity of nilotinib, dasatinib and ponatinib to a much lesser extent. In conclusion, our data suggest that wild-type ABCB1 exports imatinib more efficiently than the 1236T-2677T-3435T variant protein, providing a molecular basis for the reported association between ABCB1 polymorphisms and the response to imatinib in CML. Our results also point to a weaker impact of ABCB1 polymorphisms on the activity of nilotinib, dasatinib and ponatinib.
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Dessilly
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nadtha
authors.initials: N
authors.lastname: Panin
authors.affiliation: Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Laure
authors.initials: L
authors.lastname: Elens
authors.affiliation: Louvain centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.|Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Haufroid
authors.affiliation: De Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D000069439:Dasatinib / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D020014:K562 Cells; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; C545373:ponatinib; D000068877:Imatinib Mesylate; C498826:nilotinib; D000069439:Dasatinib