Karin Skoglund1, Samuel Boiso Moreno, Jan-Ingvar Jönsson, Svante Vikingsson, Björn Carlsson, Henrik Gréen. 1. aDepartment of Medical and Health Sciences, Division of Drug Research/Clinical Pharmacology, Faculty of Health Sciences bDepartment of Clinical and Experimental Medicine, Linköping University cDivision of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Department of Clinical Pharmacology, County Council of Östergötland dDepartment of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
Abstract
OBJECTIVE: The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (ABCG2). Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single-nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in-vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs [imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib, and bosutinib]. MATERIALS AND METHODS: ABCG2 SNPs 34G>A, 421C>A, 623T>C, 886G>C, 1574T>G, and 1582G>A were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity. RESULTS: Wild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421C>A, 623T>C, 886G>C, and 1574T>G reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity. CONCLUSION: These findings show that the ABCG2 SNPs 421C>A, 623T>C, 886G>C, and 1574T>G increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.
OBJECTIVE: The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (ABCG2). Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single-nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in-vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs [imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib, and bosutinib]. MATERIALS AND METHODS: ABCG2 SNPs 34G>A, 421C>A, 623T>C, 886G>C, 1574T>G, and 1582G>A were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity. RESULTS: Wild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421C>A, 623T>C, 886G>C, and 1574T>G reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity. CONCLUSION: These findings show that the ABCG2 SNPs 421C>A, 623T>C, 886G>C, and 1574T>G increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.
Authors: Daniel T Barratt; Hannah K Cox; Andrew Menelaou; David T Yeung; Deborah L White; Timothy P Hughes; Andrew A Somogyi Journal: Clin Pharmacokinet Date: 2017-08 Impact factor: 6.447
Authors: Alison E Fohner; Deanna J Brackman; Kathleen M Giacomini; Russ B Altman; Teri E Klein Journal: Pharmacogenet Genomics Date: 2017-11 Impact factor: 2.089
Authors: Jose J G Marin; Maria A Serrano; Maria J Monte; Anabel Sanchez-Martin; Alvaro G Temprano; Oscar Briz; Marta R Romero Journal: Int J Mol Sci Date: 2020-04-20 Impact factor: 5.923
Authors: Ruba S Darweesh; Tamam El-Elimat; Aref Zayed; Tareq N Khamis; Wahby M Babaresh; Tawfiq Arafat; Ahmed H Al Sharie Journal: BMC Pharmacol Toxicol Date: 2020-11-16 Impact factor: 2.483
Authors: Narakorn Khunweeraphong; James Mitchell-White; Dániel Szöllősi; Toka Hussein; Karl Kuchler; Ian D Kerr; Thomas Stockner; Jyh-Yeuan Lee Journal: FEBS Lett Date: 2020-10-14 Impact factor: 3.864