Development of imatinib and dasatinib resistance: dynamics of expression of drug transporters ABCB1, ABCC1, ABCG2, MVP, and SLC22A1

• Published in: Leukemia & lymphoma Vol. 52; no. 10; pp. 1980 - 1990
• Main Authors: Gromicho, Marta, Dinis, Joana, Magalhães, Marta, Fernandes, Alexandra R., Tavares, Purificação, Laires, António, Rueff, José, Rodrigues, António Sebastião
• Format: Journal Article
• Language: English
• Published: United States Informa Healthcare 01.10.2011; Taylor & Francis
• Subjects: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters - genetics; Benzamides; Chronic myeloid leukemia; Dasatinib; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - genetics; drug transporters (ABCB1, ABCC1, ABCC3, ABCG2, MVP, SLC22A1; Gene Expression Regulation, Leukemic; Humans; Imatinib Mesylate; K562 cell line; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Membrane Transport Proteins - genetics; multidrug resistance; Multidrug Resistance-Associated Proteins - genetics; Neoplasm Proteins - genetics; Organic Cation Transporter 1 - genetics; Piperazines - pharmacology; Pyrimidines - pharmacology; Thiazoles - pharmacology; Vault Ribonucleoprotein Particles - genetics
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428194.2011.584005

About 20% of patients with chronic myeloid leukemia (CML) do not respond to treatment with imatinib either initially or because of acquired resistance. To study the development of CML drug resistance, an in vitro experimental system comprising cell lines with different resistance levels was established by exposing K562 cells to increasing concentrations of imatinib and dasatinib anticancer agents. The mRNA levels of BCR- ABL1 and of genes involved in drug transport or redistribution (ABCB1, ABCC1, ABCC3, ABCG2, MVP, and SLC22A1) were measured and the ABL1 kinase domain sequenced. Results excluded BCR- ABL1 overexpression and mutations as relevant resistance mechanisms. Most studied transporters were overexpressed in the majority of resistant cell lines. Their expression pattern was dynamic: varying with resistance level and chronic drug exposure. Studied efflux transporters may have an important role at the initial stages of resistance, but after prolonged exposure and for higher doses of drugs other mechanisms might take place.