Resistance to daunorubicin, imatinib, or nilotinib depends on expression levels of ABCB1 and ABCG2 in human leukemia cells
Language English Country Ireland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24954033
DOI
10.1016/j.cbi.2014.06.009
PII: S0009-2797(14)00188-4
Knihovny.cz E-resources
- Keywords
- ABC transporters, Bcr-Abl tyrosine kinase, Drug resistance, Intracellular drug level, K562 cells, Tyrosine kinase inhibitors,
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
- ATP-Binding Cassette Transporters genetics metabolism MeSH
- Benzamides antagonists & inhibitors pharmacology therapeutic use MeSH
- K562 Cells MeSH
- Drug Resistance, Neoplasm physiology MeSH
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy MeSH
- Daunorubicin antagonists & inhibitors pharmacology therapeutic use MeSH
- Imatinib Mesylate MeSH
- Humans MeSH
- Neoplasm Proteins genetics metabolism MeSH
- ATP Binding Cassette Transporter, Subfamily B genetics metabolism MeSH
- Piperazines antagonists & inhibitors pharmacology therapeutic use MeSH
- Pyrimidines antagonists & inhibitors pharmacology therapeutic use MeSH
- Cell Survival drug effects MeSH
- Blotting, Western MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
- ATP-Binding Cassette Transporters MeSH
- ABCB1 protein, human MeSH Browser
- ABCG2 protein, human MeSH Browser
- Benzamides MeSH
- Daunorubicin MeSH
- Imatinib Mesylate MeSH
- Neoplasm Proteins MeSH
- nilotinib MeSH Browser
- ATP Binding Cassette Transporter, Subfamily B MeSH
- Piperazines MeSH
- Pyrimidines MeSH
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.
References provided by Crossref.org
The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance
