Overcoming platinum drug resistance with copper-lowering agents.
Overcoming platinum drug resistance with copper-lowering agents.
复制标题
作者：
H. Chen;M. Kuo
铂（Pt）为基础的抗肿瘤药物已成为癌症化疗的支柱在过去的三十年。虽然多种机制导致治疗失败，但药物转运缺陷是一个重要因素。人类高亲和力铜（Cu）转运蛋白-1（hCtr 1）也可以转运铂类药物，包括顺铂（cDDP）和卡铂。hCtr 1表达减少经常发生在cDDP耐药细胞系和这些药物化疗失败的癌症患者中。我们以前证明，铜螯合诱导转录因子Sp1的表达，其结合Sp1和hCtr 1的启动子，从而上调其表达，而铜过载关闭hCtr 1和Sp1的表达，通过解离Sp1从其启动子启动子。因此，哺乳动物的铜稳态转录调节内的一个环组成的Sp1，hCtr 1，和铜在一个三路相互调节的方式。这些发现表明，通过干预哺乳动物铜稳态来模块cDDP转运能力是可行的。事实上，我们发现，cDDP耐药性可以克服铜降低剂，通过增强hCtr 1表达的上调培养细胞中的Sp1。这一发现为正在进行的使用铜螯合剂克服卵巢癌化疗中cDDP耐药性的临床研究提供了机制基础。使用铜螯合剂（曲恩汀）增强卡铂治疗5例卵巢癌患者的疗效的初步研究显示了令人鼓舞的结果。这篇简短的综述描述了在癌症化疗中使用降铜剂克服铂耐药的前景。
Platinum (Pt)-based antitumor agents have been the mainstay of cancer chemotherapy for the last three decades. While multiple mechanisms are responsible for treatment failure, deficiency in drug transport is an important contributor. The human high-affinity copper (Cu) transporter-1 (hCtr1) can also transport Pt-based drugs including cisplatin (cDDP) and carboplatin. Reduced hCtr1 expression frequently occurs in cDDP-resistant cell lines and in cancer in patients who failed chemotherapy with these drugs. We previously demonstrated that Cu chelation induces the expression of transcription factor Sp1 which binds the promoters of Sp1 and hCtr1, thereby, up-regulating their expression, whereas Cu overload shuts down hCtr1 and Sp1 expression by dissociating Sp1 from their promoter promoters. Thus, mammalian Cu homeostasis is transcriptionally regulated within a loop consisting of Sp1, hCtr1, and Cu in a three-way mutually regulated manner. These findings suggest that it is feasible to module cDDP transport capacity through intervention of mammalian Cu homeostasis. Indeed, we found that cDDP resistance can be overcome by Cu-lowering agents through enhanced hCtr1 expression by up-regulation of Sp1 in cultured cells. This discovery provided a mechanistic basis for the ongoing clinical study using Cu chelator to overcome cDDP resistance in ovarian cancer chemotherapy. Preliminary study using copper chelator (trientine) for enhancing the treatment efficacy of carboplatin in 5 ovarian cancer patients showed encouraging results. This short review describes the perspectives of using Cu-lowering agents in overcoming Pt resistance in cancer chemotherapy.