Combined Use of Anticancer Drugs and an Inhibitor of Multiple Drug Resistance-Associated Protein-1 Increases Sensitivity and Decreases Survival of Glioblastoma Multiforme Cells In Vitro
Combined Use of Anticancer Drugs and an Inhibitor of Multiple Drug Resistance-Associated Protein-1 Increases Sensitivity and Decreases Survival of Glioblastoma Multiforme Cells In Vitro
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DOI：
10.1007/s11064-011-0464-8
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发表时间：
2011-08-01
影响因子：
4.4
通讯作者：
Quezada, Claudia
中科院分区：
文献类型：
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作者：
Peignan, Lilia;Garrido, Wallys;Quezada, Claudia
多形性胶质母细胞瘤（GBM）是一种脑肿瘤，其特征是具有非常高的化疗耐药性和浸润能力。迄今为止，替莫唑胺化疗对提高患者生存率的作用很小。化疗耐药性的最重要机制之一是通过ATP结合盒超家族中某些蛋白质的活性产生的，这些蛋白质从细胞中挤出抗肿瘤药物或其代谢产物。我们发现多药耐药相关蛋白1（Mrp 1）在多形性胶质母细胞瘤活检组织以及T98 G和G44细胞系中表达增加。还通过测量荧光底物CFDA的挤出证实了该转运蛋白的活性。暴露于替莫唑胺、长春新碱和依托泊苷后，GBM细胞的敏感性较低，在这些药物的治疗浓度下观察到细胞活力降低低于20%。然而，联合暴露于长春新碱或依托泊苷与Mrp1抑制剂有效地降低细胞活力高达80%。我们的结论是，细胞与Mrp1活性抑制剂的化疗增敏可能是一种有效的工具，用于治疗人类GBM。
Glioblastoma multiforme (GBM) is a brain tumour characterised by a remarkably high chemoresistance and infiltrating capability. To date, chemotherapy with temozolomide has contributed only poorly to improved survival rates in patients. One of the most important mechanisms of chemoresistance comes about through the activity of certain proteins from the ATP-binding cassette superfamily that extrudes antitumour drugs, or their metabolites, from cells. We identify an increased expression of the multiple drug resistance-associated protein 1 (Mrp1) in glioblastoma multiforme biopsies and in T98G and G44 cell lines. The activity of this transporter was also confirmed by measuring the extrusion of the fluorescent substrate CFDA. The sensitivity of GBM cells was low upon exposure to temozolomide, vincristine and etoposide, with decreases in cell viability of below 20% seen at therapeutic concentrations of these drugs. However, combined exposure to vincristine or etoposide with an inhibitor of Mrp1 efficiently decreased cell viability by up to 80%. We conclude that chemosensitization of cells with inhibitors of Mrp1 activity might be an efficient tool for the treatment of human GBM.