Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis.
Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis.
复制标题
DOI：
10.3390/ijms19051486
复制
发表时间：
2018-05-16
影响因子：
5.6
通讯作者：
Chen HHW
中科院分区：
文献类型：
--
作者：
Lai YH;Kuo C;Kuo MT;Chen HHW
铂（Pt）为基础的抗肿瘤药物已有效地治疗许多人类恶性肿瘤。药物输入、细胞内改组和输出-分别由高亲和力铜（Cu）转运蛋白（hCtr 1）、铜分子伴侣（Ato x1）和铜输出蛋白（ATP 7A和ATP 7 B）进行-累积地促进铂类药物（包括顺铂和卡铂，但不包括奥沙利铂）的化疗敏感性。这整个系统也可以处理铂药物之间的相互作用，通过铂和含巯基的氨基酸残基在这些蛋白质;相互作用的强烈影响细胞的氧化还原调节剂，如谷胱甘肽。hCtr 1表达由急性铜剥夺诱导，并且该诱导受转录因子特异性蛋白1（Sp1）的调节，Sp1本身也受铜浓度变化的调节。铜取代锌（Zn）的锌指（ZF）结构域的Sp1和失活的DNA结合，而铜剥夺增强Sp1-DNA的相互作用，并增加Sp1的表达，这反过来上调hCtr 1的协调。由于共享的转运系统，铂类药物的化疗敏感性可以通过靶向铜转运蛋白来调节。降铜剂（曲恩汀）联合铂类药物（卡铂）已用于临床研究，以克服铂耐药性。未来的研究应旨在进一步开发有效的铂药物保留策略，以提高治疗效果。
Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting—carried out by the high-affinity copper (Cu) transporter (hCtr1), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively—cumulatively contribute to the chemosensitivity of Pt drugs including cisplatin and carboplatin, but not oxaliplatin. This entire system can also handle Pt drugs via interactions between Pt and the thiol-containing amino acid residues in these proteins; the interactions are strongly influenced by cellular redox regulators such as glutathione. hCtr1 expression is induced by acute Cu deprivation, and the induction is regulated by the transcription factor specific protein 1 (Sp1) which by itself is also regulated by Cu concentration variations. Copper displaces zinc (Zn) coordination at the zinc finger (ZF) domains of Sp1 and inactivates its DNA binding, whereas Cu deprivation enhances Sp1-DNA interactions and increases Sp1 expression, which in turn upregulates hCtr1. Because of the shared transport system, chemosensitivity of Pt drugs can be modulated by targeting Cu transporters. A Cu-lowering agent (trientine) in combination with a Pt drug (carboplatin) has been used in clinical studies for overcoming Pt-resistance. Future research should aim at further developing effective Pt drug retention strategies for improving the treatment efficacy.
登录
查看更多内容
影响因子：
3.6
作者：
Chen, Helen H. W.;Song, Im-Sook;Kuo, Macus Tien
通讯作者：
Kuo, Macus Tien
DOI：
10.1016/j.bbrc.2017.07.064
发表时间：
2017-09-09
影响因子：
3.1
作者：
Celauro, Emanuele;Mukaj, Amisa;Wittung-Stafshede, Pernilla
通讯作者：
Wittung-Stafshede, Pernilla
影响因子：
15
作者：
Boal AK;Rosenzweig AC
通讯作者：
Rosenzweig AC
影响因子：
11.2
作者：
Brady DC;Crowe MS;Greenberg DN;Counter CM
通讯作者：
Counter CM
DOI：
10.1155/2010/430939
发表时间：
2010-01-01
期刊：
Metal-Based Drugs
影响因子：
--
作者：
Chen, Helen H. W.;Kuo, Macus Tien
通讯作者：
Kuo, Macus Tien