Multidrug resistance-associated protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine sulfoximine.
Multidrug resistance-associated protein 1 (MRP1) mediated vincristine resistance: effects of N-acetylcysteine and Buthionine sulfoximine.
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多药耐药相关蛋白 1 (MRP1) 介导的长春新碱耐药性：N-乙酰半胱氨酸和丁硫氨酸亚磺酰亚胺的作用。
DOI：
10.1186/1475-2867-5-22
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发表时间：
2005-07-24
影响因子：
5.8
通讯作者：
Ozben T
中科院分区：
文献类型：
--
作者：
Akan I;Akan S;Akca H;Savas B;Ozben T
由多药耐药相关蛋白1(MRP1)介导的多药耐药减少了细胞内的药物积累。MRP1参与多药耐药的确切机制尚不清楚，尽管谷胱甘肽(GSH)可能在耐药发生中起作用。N-乙酰半胱氨酸(NAC)是一种谷胱甘肽前体药物。丁硫氨酸(S，右)-亚磺胺(BSO)是谷胱甘肽合成的抑制剂。本研究旨在探讨NAC和BSO对MRP1介导的人胚胎肾(HEK293)及其转导的293MRP细胞对长春新碱耐药的影响。以人胚胎肾(HEK293)细胞为研究对象，构建了MRP1全长编码基因的重组表达载体。在NAC和/或BSO存在或不存在的情况下，两种细胞都与长春新碱孵育。测定两种细胞在不同培养条件下的存活率。用不同药物孵育两种细胞，测定细胞提取液中谷胱甘肽S转移酶和谷胱甘肽过氧化物酶的含量。N-乙酰半胱氨酸增加了两种细胞对长春新碱的耐药性，BSO降低了NAC增强MRP1介导的长春新碱耐药性，提示MRP1介导的长春新碱耐药性的诱导依赖于GSH。长春新碱可降低细胞内GSH浓度，提高GPx活性。NAC可降低谷胱甘肽S转移酶活性。结果表明，NAC和BSO在MRP1介导的长春新碱耐药中具有相反的作用，BSO有望成为MRP1过表达肿瘤细胞的化疗增强剂。
Multidrug resistance mediated by the multidrug resistance-associated protein 1 (MRP1) decreases cellular drug accumulation. The exact mechanism of MRP1 involved multidrug resistance has not been clarified yet, though glutathione (GSH) is likely to have a role for the resistance to occur. N-acetylcysteine (NAC) is a pro-glutathione drug. DL-Buthionine (S,R)-sulfoximine (BSO) is an inhibitor of GSH synthesis. The aim of our study was to investigate the effect of NAC and BSO on MRP1-mediated vincristine resistance in Human Embryonic Kidney (HEK293) and its MRP1 transfected 293MRP cells. Human Embryonic Kidney (HEK293) cells were transfected with a plasmid encoding whole MRP1 gene. Both cells were incubated with vincristine in the presence or absence of NAC and/or BSO. The viability of both cells was determined under different incubation conditions. GSH, Glutathione S-Transferase (GST) and glutathione peroxidase (GPx) levels were measured in the cell extracts obtained from both cells incubated with different drugs. N-acetylcysteine increased the resistance of both cells against vincristine and BSO decreased NAC-enhanced MRP1-mediated vincristine resistance, indicating that induction of MRP1-mediated vincristine resistance depends on GSH. Vincristine decreased cellular GSH concentration and increased GPx activity. Glutathione S-Transferase activity was decreased by NAC. Our results demonstrate that NAC and BSO have opposite effects in MRP1 mediated vincristine resistance and BSO seems a promising chemotherapy improving agent in MRP1 overexpressing tumor cells.
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DOI：
10.1073/pnas.91.26.13033
发表时间：
1994-12-20
影响因子：
11.1
作者：
MULLER, M;MEIJER, C;JANSEN, PLM
通讯作者：
JANSEN, PLM
影响因子：
3.9
作者：
James, LP;Mayeux, PR;Hinson, JA
通讯作者：
Hinson, JA
影响因子：
11.2
作者：
Mori, K;Shibanuma, M;Nose, K
通讯作者：
Nose, K
影响因子：
5.7
作者：
Aizawa, S;Ookawa, K;Tsuchida, S
通讯作者：
Tsuchida, S
影响因子：
4.7
作者：
Morrow, CS;Diah, S;Townsend, AJ
通讯作者：
Townsend, AJ