Peng Xing-Xiang, Tiwari Amit K, Wu Hsiang-Chun, Chen Zhe-Sheng
Department of Pharmaceutical Sciences, St. John's University, Queens, NY 11439, USA.
Chin J Cancer. 2012 Feb;31(2):110-8. doi: 10.5732/cjc.011.10327. Epub 2011 Nov 18.
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.
伊马替尼是一种断裂簇集区（BCR）-阿贝尔逊鼠白血病（ABL）酪氨酸激酶抑制剂（TKI），它彻底改变了慢性粒细胞白血病（CML）的治疗方式。然而，多药耐药（MDR）的出现限制了伊马替尼的使用。在本研究中，我们旨在探究CML细胞对伊马替尼产生耐药性的机制。因此，我们通过逐步筛选过程建立了一种对伊马替尼耐药的人CML细胞系（K562-伊马替尼）。在对这些细胞的表型进行表征时，我们发现K562-伊马替尼细胞对伊马替尼的耐药性比亲代K562细胞高124.6倍。此外，这些细胞对第二代和第三代BCR-ABL TKIs也具有交叉耐药性。蛋白质免疫印迹分析和逆转录-聚合酶链反应（RT-PCR）表明，K562-伊马替尼细胞中P-糖蛋白（P-gp）和MDR1 mRNA水平升高。此外，K562-伊马替尼细胞中[14C]6-巯基嘌呤（6-MP）的积累减少，而[14C]6-MP的ATP依赖性外排和[3H]甲氨蝶呤转运增加。这些数据表明，P-gp的过表达可能在CML K562-伊马替尼细胞对伊马替尼的获得性耐药中起关键作用。
