Buthionine sulphoximine-mediated sensitisation of etoposide-resistant human breast cancer MCF7 cells overexpressing the multidrug resistance-associated protein involves increased drug accumulation.
Buthionine sulphoximine-mediated sensitisation of etoposide-resistant human breast cancer MCF7 cells overexpressing the multidrug resistance-associated protein involves increased drug accumulation.
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DOI：
10.1038/bjc.1995.144
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发表时间：
1995-04
影响因子：
8.8
通讯作者：
Cowan, K H
中科院分区：
文献类型：
--
作者：
Schneider, E;Yamazaki, H;Sinha, B K;Cowan, K H
依托泊苷耐药的人MCF 7乳腺癌细胞（MCF 7/VP）与丁硫氨磺酰亚胺（BSO）的预孵育导致其对依托泊苷和长春新碱的敏感性。化疗增敏伴随着细胞内药物水平升高。相反，同时暴露于BSO不会导致药物蓄积增加。当用BSO处理敏感的野生型MCF 7/WT细胞时，也观察到类似的但数量较小的作用。与其对药物蓄积的影响一致，BSO预处理也增加了VP-16刺激的DNA拓扑异构酶II和细胞DNA之间的可切割复合物的形成。BSO处理还导致MCF 7/VP中酸可沉淀VP-16水平显著增加，但不导致MCF 7/WT细胞中酸可沉淀VP-16水平显著增加。相比之下，在MCF 7/WT和MCF 7/VP细胞的BSO处理后，未观察到BSO对药物外排的明显影响，药物保留仅轻微增加，并且未检测到两种细胞系之间的差异。因此，BSO的化疗增敏作用似乎是通过增加细胞内药物浓度和/或蛋白结合介导的。
Preincubation of etoposide-resistant human MCF7 breast cancer cells (MCF7/VP) with buthionine sulphoximine (BSO) resulted in their sensitisation to etoposide and vincristine. Chemosensitisation was accompanied by elevated intracellular drug levels. In contrast, simultaneous exposure to BSO did not result in increased drug accumulation. Similar, but quantitatively smaller, effects were also observed when sensitive wild-type MCF7/WT cells were treated with BSO. In agreement with its effect on drug accumulation, BSO pretreatment also increased VP-16-stimulated cleavable complex formation between DNA topoisomerase II and cellular DNA. BSO treatment also led to a significant increase in acid-precipitable VP-16 levels in MCF7/VP, but not MCF7/WT cells. In contrast, no clear effects of BSO on drug efflux were observed and drug retention was only minimally increased after BSO treatment of both MCF7/WT and MCF7/VP cells and no difference between the two cell lines was detected. Thus, chemosensitisation by BSO appeared to be mediated through increased intracellular drug concentrations and/or protein binding.