Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells / 癌症
Chinese Journal of Cancer
;
(12): 110-118, 2012.
Article
in English
| WPRIM
| ID: wpr-294448
ABSTRACT
Imatinib, a breakpoint cluster region (BCR)-Abelson murine leukemia(ABL) tyrosine kinase inhibitor (TKI), has revolutionized the treatment of chronic myelogenous leukemia (CML). However, development of multidrug resistance(MDR) limits the use of imatinib. In the present study, we aimed to investigate the mechanisms of cellular resistance to imatinib in CML. Therefore, we established an imatinib-resistant human CML cell line(K562-imatinib) through a stepwise selection process. While characterizing the phenotype of these cells, we found that K562-imatinib cells were 124.6-fold more resistant to imatinib than parental K562 cells. In addition, these cells were cross-resistant to second- and third-generation BCR-ABL TKIs. Western blot analysis and reverse transcription-polymerase chain reaction(RT-PCR) demonstrated that P-glycoprotein(P-gp) and MDR1 mRNA levels were increased in K562-imatinib cells. In addition, accumulation of [14C]6-mercaptopurine (6-MP) was decreased, whereas the ATP-dependent efflux of [14C]6-MP and [3H]methotrexate transport were increased in K562-imatinib cells. These data suggest that the overexpression of P-gp may play a crucial role in acquired resistance to imatinib in CML K562-imatinib cells.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Pharmacology
/
Piperazines
/
Pyrimidines
/
Benzamides
/
Protein-Tyrosine Kinases
/
RNA, Messenger
/
Gene Expression Regulation, Neoplastic
/
Methotrexate
/
Fusion Proteins, bcr-abl
/
Drug Resistance, Multiple
Limits:
Humans
Language:
English
Journal:
Chinese Journal of Cancer
Year:
2012
Type:
Article
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