Instituto de Bioquímica, Facultad de Ciencias, Universidad Austral de Chile, Campus Isla Teja s/n, P.O. box 567, Valdivia, Chile.
Neurochem Res. 2011 Aug;36(8):1397-406. doi: 10.1007/s11064-011-0464-8. Epub 2011 May 5.
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.
多形性胶质母细胞瘤（GBM）是一种具有极高化疗耐药性和浸润能力的脑肿瘤。迄今为止，替莫唑胺化疗仅对提高患者的生存率贡献不大。化学耐药性的最重要机制之一是通过 ATP 结合盒超家族的某些蛋白质的活性来实现的，这些蛋白质将抗肿瘤药物或其代谢物从细胞中排出。我们在多形性胶质母细胞瘤活检标本以及 T98G 和 G44 细胞系中发现多药耐药相关蛋白 1（Mrp1）的表达增加。通过测量荧光底物 CFDA 的外排来证实该转运蛋白的活性。GBM 细胞对替莫唑胺、长春新碱和依托泊苷的敏感性较低，这些药物的治疗浓度下细胞活力下降低于 20%。然而，长春新碱或依托泊苷与 Mrp1 抑制剂联合暴露可有效将细胞活力降低多达 80%。我们得出结论，用 Mrp1 活性抑制剂对细胞进行化疗增敏可能是治疗人类 GBM 的有效工具。
