Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells
Inhibition of thioredoxin reductase by auranofin induces apoptosis in cisplatin-resistant human ovarian cancer cells
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DOI：
10.1016/j.freeradbiomed.2006.12.021
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发表时间：
2007-03-15
影响因子：
7.4
通讯作者：
Rigobello, Maria Pia
中科院分区：
文献类型：
--
作者：
Marzano, Christine;Gandin, Valentina;Rigobello, Maria Pia
顺铂是一种有效的抗肿瘤药物，可用于治疗多种癌症。然而，对顺铂产生耐药性是一个严重的临床问题。研究了金诺芬（一种临床上用作抗风湿剂的金 (I) 化合物）对顺铂敏感 (2008) 和耐药 (C13*) 癌细胞的影响。金诺芬在降低细胞活力方面比顺铂更有效，其作用在 C13* 细胞中尤其明显，表明不发生交叉耐药。此外，金诺芬能够比 2008 细胞更有效地渗透 C13* 细胞。金诺芬治疗决定了两种细胞系中细胞色素 c 的一致释放，而顺铂仅对敏感细胞有效。金诺芬和顺铂均可诱导 2008 细胞凋亡，而在 C13* 细胞中只有金诺芬有效。细胞凋亡伴随着过氧化氢产生的增加，但过氧化氢会被 N-乙酰基-L-半胱氨酸抑制。在耐药细胞中，H2O2 的产生被硫氧还蛋白还原酶的大量过度表达所抵消，硫氧还蛋白还原酶构成了金诺芬抑制作用的首选靶点。金诺芬的这种特殊作用可能合理化其克服人类卵巢癌细胞顺铂耐药性的能力。 (c) 2006 Elsevier Inc. 保留所有权利。
Cisplatin is an effective antitumor agent for the treatment of several carcinomas. However, the development of resistance to cisplatin represents a serious clinical problem. The effects of auranofin, a gold(I) compound clinically used as an antirheumatic agent, on cisplatin-sensitive (2008) and-resistant (C13*) cancer cells were studied. Auranofin is more effective than cisplatin in decreasing cell viability and its action is particularly marked in C13* cells, indicating that no cross-resistance occurs. Furthermore, auranofin is able to permeate C13* cells more efficiently than 2008 cells. Treatment with auranofin determines a consistent release of cytochrome c in both cell lines, while cisplatin is effective only in sensitive cells. Both auranofin and cisplatin induce apoptosis in 2008 cells, while in C13* cells only auranofin is effective. Apoptosis is accompanied by an increased production of hydrogen peroxide that, however, is inhibited by N-acetyl-L-cysteine. In resistant cells, H2O2 production is counteracted by a large overexpression of thioredoxin reductase that constitutes the preferred target of the inhibitory action of auranofin. This specific effect of auranofin might rationalize its ability in overcoming cisplatin resistance in human ovarian cancer cells. (c) 2006 Elsevier Inc. All rights reserved.