Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia, Chile.
Biochem Biophys Res Commun. 2011 Jul 22;411(1):62-8. doi: 10.1016/j.bbrc.2011.06.087. Epub 2011 Jun 17.
Glioblastoma multiforme (GBM) is the most aggressive of brain tumors and is extremely insensitive to anticancer drugs. Studies have attributed the ABC transporter Mrp1 (ABCC1, multiple-drug resistance protein 1) with conferring chemoresistance in this tumor by extrusion of a wide spectrum of anticancer drugs. Therefore it is crucial to search for and investigate inhibitors of Mrp1 activity in GBM cells, particularly those that could be safe as chemosensitizers to anticancer drugs in clinical studies. We find that in primary cultured or T98G GBM cells exposed to therapeutic plasma concentrations of FK506 (tacrolimus), the expression of Mrp1 was decreased in a dose-dependent manner. The activity of this transporter, measured by CFDA fluorescent substrate extrusion, decreased significantly in primary cultured GBM cells on exposure to FK506 at concentrations of 15 ng/ml. When GBM cells were exposed to anticancer drugs vincristine, etoposide or taxol, cell viability was not affected. However when the anticancer drugs were assayed in combination with FK506, cell viability was significantly decreased by as much as 50% in GBM primary culture. We conclude that FK506 could be a valuable tool for chemosensitization of GBM cells, offering a possible improvement to the current poor therapy available for high-grade human gliomas.
多形性胶质母细胞瘤（GBM）是最具侵袭性的脑肿瘤，对抗癌药物极其不敏感。研究表明，ABC 转运蛋白 Mrp1（ABCC1，多药耐药蛋白 1）通过将广泛的抗癌药物外排，赋予了这种肿瘤的耐药性。因此，寻找和研究 GBM 细胞中 Mrp1 活性的抑制剂至关重要，特别是那些在临床研究中作为抗癌药物增敏剂可能安全的抑制剂。我们发现，在暴露于治疗性血浆浓度 FK506（他克莫司）的原代培养或 T98G GBM 细胞中，Mrp1 的表达呈剂量依赖性降低。用 CFDA 荧光底物外排法测量的该转运蛋白的活性在原代培养的 GBM 细胞暴露于 15ng/ml 的 FK506 时显著降低。当将抗癌药物长春新碱、依托泊苷或紫杉醇暴露于 GBM 细胞时，细胞活力不受影响。然而，当将抗癌药物与 FK506 联合检测时，GBM 原代培养物中的细胞活力下降了多达 50%。我们得出结论，FK506 可能是 GBM 细胞化学增敏的有价值工具，为目前治疗高级别人类神经胶质瘤的现有治疗方法提供了可能的改善。
