Baran Yusuf, Gür Bala, Kaya Pelin, Ural Ali Uğur, Avcu Ferit, Gündüz Ufuk
Middle East Technical University, Department of Biological Sciences, 06531 Ankara, Turkey.
Hematology. 2007 Dec;12(6):511-7. doi: 10.1080/10245330701562535.
The major problem in the treatment of acute myeloid leukemia (AML) patients results from multidrug resistance to administered anticancer agents. Drug resistance proteins, MDR1 and MRP1, which work as drug efflux pumps, can mediate the multidrug resistance of human leukemia cells. In this study, the mechanisms of resistance to doxorubicin-induced cell death in human HL60 AML cells were examined. Continuous exposure of cells to step-wise increasing concentrations of doxorubicin resulted in the selection of HL60/DOX cells, which expressed about 10.7-fold resistance as compared to parental sensitive cells. The expression analyses of MRP1 and MDR1 drug efflux proteins in doxorubicin-sensitive and -resistant HL60 cells revealed that there was an upregulation of MRP1 gene in HL60/DOX cells as compared to parental sensitive cells. On the other hand, while there was no expression of MDR1 gene in parental cells, the expression of MDR1 gene was upregulated in HL60/DOX cells. HL60/DOX cells also showed cross-resistance to cytosine arabinoside (Ara-c). This resistance was reversed by a combination therapy of Ara-c and cyclosporine A. However, the expression levels of CD15 and CD16 surface markers were significantly decreased in HL60/DOX cells.
急性髓系白血病（AML）患者治疗中的主要问题源于对所施用抗癌药物的多药耐药性。作为药物外排泵发挥作用的耐药蛋白MDR1和MRP1可介导人类白血病细胞的多药耐药性。在本研究中，对人HL60 AML细胞中对阿霉素诱导的细胞死亡的耐药机制进行了研究。将细胞连续暴露于逐步增加浓度的阿霉素中，导致选择出HL60/DOX细胞，与亲代敏感细胞相比，其表现出约10.7倍的耐药性。对阿霉素敏感和耐药的HL60细胞中MRP1和MDR1药物外排蛋白的表达分析表明，与亲代敏感细胞相比，HL60/DOX细胞中MRP1基因上调。另一方面，虽然亲代细胞中没有MDR1基因的表达，但HL60/DOX细胞中MDR1基因的表达上调。HL60/DOX细胞对阿糖胞苷（Ara-c）也表现出交叉耐药性。阿糖胞苷和环孢素A联合治疗可逆转这种耐药性。然而，HL60/DOX细胞中CD15和CD16表面标志物的表达水平显著降低。
