ATP Binding Cassette C1 (ABCC1/MRP1)-mediated drug efflux contributes to disease progression in T-lineage acute lymphoblastic leukemia.
ATP Binding Cassette C1 (ABCC1/MRP1)-mediated drug efflux contributes to disease progression in T-lineage acute lymphoblastic leukemia.
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DOI：
10.4236/health.2013.55a005
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发表时间：
2013-05-01
期刊：
影响因子：
2.1
通讯作者：
Larson, Richard S
中科院分区：
文献类型：
--
作者：
Winter, Stuart S;Ricci, Jerec;Larson, Richard S
目的：在急性淋巴细胞白血病（ALL）中，多药耐药通常由atp酶结合盒（ABC）蛋白介导，主要涉及ABCB1（多药耐药1，MDR1）和ABCC1（多药耐药蛋白1，MRP1）。然而，ABCB1和ABCC1的差异作用之间的直接比较一直很困难，因为尚未开发出具有这些转运蛋白差异表达的相同细胞系。实验设计：在这项研究中，我们开发并比较了选择性过表达ABCB1和ABCC1的Jurkat细胞系的生物学特征。长春新碱（VCR）在治疗t系ALL （T-ALL）中起着重要作用，通常是新诊断患者的第一种药物。由于其在治疗中的重要性，我们向Jurkat细胞提供了逐渐增加的亚致死剂量的VCR，并将我们的观察扩展到新诊断的T-ALL患者的表达谱。结果：我们发现vcr耐药细胞过表达ABCC1近30倍。钙黄素AM试验证实，VCR耐药细胞积极挤压VCR， abcc1介导的耐药与其他T-ALL诱导剂相比具有不同的多药耐药谱。阻断ABCC1输出的siRNA实验证实，体外可以逆转VCR抗性。对92名接受儿童肿瘤组III期研究8704/9404治疗的新诊断T-ALL患者的t淋巴母细胞分析显示，除一例外，诱导失败可通过ABCB1或ABCC1的过度表达来解释。结论：综上所述，这些结果表明，ABC转运蛋白的过表达在介导T-ALL治疗失败中起着重要作用，并强调了对诱导失败的患者或复发疾病患者采用替代治疗方法的必要性。
PURPOSE: In acute lymphoblastic leukemia (ALL), multidrug resistance is often mediated by ATPase Binding Cassette (ABC) proteins, which principally involve ABCB1 (multidrug resistance 1, MDR1) and ABCC1 (multidrug resistance protein 1, MRP1). However, direct comparisons between the differential effects of ABCB1 and ABCC1 have been difficult, since identical cell lines with differential expression of these transporters have not been developed.EXPERIMENTAL DESIGN: In this study, we developed and compared the biological profiles of Jurkat cell lines that selectively over-expressed ABCB1 and ABCC1. Vincristine (VCR) plays an important role in the treatment of T-lineage ALL (T-ALL), and is often the first drug given to newly-diagnosed patients. Because of its importance in treatment, we provided escalating, sub-lethal doses of VCR to Jurkat cells, and extended our observations to expression profiling of newly diagnosed patients with T-ALL.RESULTS: We found that VCR-resistant cells over-expressed ABCC1 nearly 30-fold. The calcein AM assay confirmed that VCR-resistant cells actively extruded VCR, and that ABCC1-mediated drug resistance conferred a different spectrum of multidrug resistance than other T-ALL induction agents. siRNA experiments that blocked ABCC1 export confirmed that VCR resistance could be reversed in vitro. Analyses of T-lymphoblasts obtained from 92 newly diagnosed T-ALL patients treated on Children's Oncology Group Phase III studies 8704/9404 showed that induction failure could be explained in all but one case by the over-expression of ABCB1 or ABCC1.CONCLUSIONS: Taken together, these results suggest that over-expression of ABC transporters plays a contributing role in mediating treatment failure in T-ALL, and underscore the need to employ alternate treatment approaches in patients for whom induction failed or for those with relapsed disease.