Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy.
Targeting drug transport mechanisms for improving platinum-based cancer chemotherapy.
复制标题
针对改善铂基癌症化学疗法的药物传输机制。
DOI：
10.1517/14728222.2015.1043269
复制
发表时间：
2015
影响因子：
5.8
通讯作者：
Kuo MT
中科院分区：
文献类型：
--
作者：
Chen HH;Chen WC;Liang ZD;Tsai WB;Long Y;Aiba I;Fu S;Broaddus R;Liu J;Feun LG;Savaraj N;Kuo MT
基于铂（Pt）的抗肿瘤药物仍然是治疗许多人类恶性肿瘤的重要化疗药物。人高亲和力铜转运蛋白1（hCtr1）的表达升高，导致Pt药物转运进入细胞增强，已被证明与改善的治疗效果相关。因此，靶向hCtr1上调是一种有吸引力的策略，用于改善基于Pt的癌症化疗的治疗效果。hCtr1表达的调节细胞铜稳态进行了讨论。卵巢癌对铂类药物的内在敏感性与hCtr1表达升高有关。本文综述了降铜药物增强hCtr1介导的顺铂转运的机制。评价了铜螯合策略在通过增强hCtr1表达克服cDDP抗性中的应用。虽然已经提出了通过细胞铜生物利用度调节hCtr1的转录和翻译后机制，但仍然需要详细了解通过铜稳态调节hCtr1的分子机制。最近的临床研究中使用的铜降低剂在增强hCtr1介导的药物转运已经取得了渐进的改善，克服铂耐药性。需要进一步改进确定可从治疗中获益的患者亚群的预测指标。
Platinum (Pt)-based antitumor agents remain important chemotherapeutic agents for treating many human malignancies. Elevated expression of the human high-affinity copper transporter 1 (hCtr1), resulting in enhanced Pt drug transport into cells, has been shown to be associated with improved treatment efficacy. Thus, targeting hCtr1 upregulation is an attractive strategy for improving the treatment efficacy of Pt-based cancer chemotherapy. Regulation of hCtr1 expression by cellular copper homeostasis is discussed. Association of elevated hCtr1 expression with intrinsic sensitivity of ovarian cancer to Pt drugs is presented. Mechanism of copper-lowering agents in enhancing hCtr1-mediated cis-diamminedichloroplatinum (II) (cisplatin, cDDP) transport is reviewed. Applications of copper chelation strategy in overcoming cDDP resistance through enhanced hCtr1 expression are evaluated. While both transcriptional and posttranslational mechanisms of hCtr1 regulation by cellular copper bioavailability have been proposed, detailed molecular insights into hCtr1 regulation by copper homeostasis remain needed. Recent clinical study using a copper-lowering agent in enhancing hCtr1-mediated drug transport has achieved incremental improvement in overcoming Pt drug resistance. Further improvements in identifying predictive measures in the subpopulation of patients that can benefit from the treatment are needed.