title: Resistance to daunorubicin, imatinib, or nilotinib depends on expression levels of ABCB1 and ABCG2 in human leukemia cells.
abstract: The effect of ABCB1 (P-gp, (P-glycoprotein), MDR1) and ABCG2 (BCRP1, (breast cancer resistance protein 1)) expressions on cell resistance to daunorubicin (DRN), imatinib, and nilotinib was studied in human leukemia cells. We used a set of cells derived from a parental K562 cell line, expressing various levels of ABCB1 and ABCG2, respectively. The function of ABCB1 and ABCG2 was confirmed using calcein AM and pheophorbide A accumulation assays, respectively. These assays indicated distinct differences in activities of ABCB1 and ABCG2 which corresponded to their expression levels. We observed that the resistance to DRN and imatinib was proportional to the expression level of ABCB1. Similarly, the resistance to nilotinib and imatinib was proportional to the expression level of ABCG2. Importantly, K562/DoxDR05 and K562/ABCG2-Z cells with the lowest expressions of ABCB1 and ABCG2, respectively, failed to reduce the intracellular levels of imatinib to provide a significant resistance to this drug. However, the K562/DoxDR05 and K562/ABCG2-Z cells significantly decreased the intracellular levels of DRN and nilotinib, respectively, thereby mediating significant resistances to these drugs. Only cells which expression of ABCB1 or ABCG2 exceeded a certain level exhibited a significantly decreased intracellular level of imatinib, and this effect was accompanied by a significantly increased resistance to this drug. Our results clearly indicated that resistance to anticancer drugs mediated by main ABC transporters, ABCB1 and ABCG2, strongly depends on their expressions at protein levels. Importantly, resistance for one drug might be maintained while resistance for other ones might become undetectable at low transporter expression levels.
authors: Department of Biology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
authors: Petr
authors: P
authors: Kosztyu
authors: Department of Biology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
authors: Romana
authors: R
authors: Bukvova
authors: Department of Biology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
authors: Petr
authors: P
authors: Dolezel
authors: Department of Biology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic. Electronic address: mlejnek_petr@volny.cz.
authors: Petr
authors: P
authors: Mlejnek
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib; D003630:Daunorubicin
keywords: ABC transporters; Bcr-Abl tyrosine kinase; Drug resistance; Intracellular drug level; K562 cells; Tyrosine kinase inhibitors