Department of Medicine, Moores UCSD Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
Mol Pharmacol. 2010 Jun;77(6):887-94. doi: 10.1124/mol.109.063172. Epub 2010 Feb 16.
Multiple lines of evidence indicate that the platinum-containing cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis. The cytotoxicity of the platinum drugs is directly related to how much drug enters the cell, and almost all cells that have acquired resistance to the platinum drugs exhibit reduced drug accumulation. The major copper influx transporter, copper transporter 1 (CTR1), has now been shown to control the tumor cell accumulation and cytotoxic effect of cisplatin, carboplatin, and oxaliplatin. There is a good correlation between change in CTR1 expression and acquired cisplatin resistance among ovarian cancer cell lines, and genetic knockout of CTR1 renders cells resistant to cisplatin in vivo. The expression of CTR1 is regulated at the transcriptional level by copper via Sp1 and at the post-translational level by the proteosome. Copper and cisplatin both trigger the down-regulation of CTR1 via a process that involves ubiquitination and proteosomal degradation and requires the copper chaperone antioxidant protein 1 (ATOX1). The cisplatin-induced degradation of CTR1 can be blocked with the proteosome inhibitor bortezomib, and this increases the cellular uptake and the cytotoxicity of cisplatin in a synergistic manner. Copper and platinum(II) have similar sulfur binding characteristics, and the presence of stacked rings of methionines and cysteines in the CTR1 trimer suggest a mechanism by which CTR1 selectively transports copper and the platinum-containing drugs via sequential transchelation reactions similar to the manner in which copper is passed from ATOX1 to the copper efflux transporters.
多种证据表明，含铂抗癌药物进入细胞后，分布到各种细胞亚区，并通过进化来管理铜稳态的转运体从细胞中输出。铂类药物的细胞毒性与进入细胞的药物量直接相关，几乎所有对铂类药物产生耐药性的细胞都表现出药物积累减少。主要的铜内流转运体铜转运蛋白 1（CTR1）现已被证明可以控制顺铂、卡铂和奥沙利铂在肿瘤细胞中的积累和细胞毒性作用。CTR1 表达的变化与卵巢癌细胞系获得性顺铂耐药之间存在良好的相关性，并且 CTR1 的基因敲除使细胞对顺铂在体内产生耐药性。CTR1 的表达在转录水平上受铜通过 Sp1 调控，在翻译后水平上受蛋白酶体调控。铜和顺铂都通过泛素化和蛋白酶体降解过程下调 CTR1，这一过程需要铜伴侣抗氧化蛋白 1（ATOX1）。顺铂诱导的 CTR1 降解可以用蛋白酶体抑制剂硼替佐米阻断，这以协同方式增加顺铂的细胞摄取和细胞毒性。铜和铂（II）具有相似的硫结合特征，CTR1 三聚体中存在堆积的蛋氨酸和半胱氨酸环，这表明 CTR1 通过顺序转金属化反应选择性地转运铜和含铂药物的机制，类似于 ATOX1 将铜传递给铜外排转运体的方式。
