Kuo Macus Tien, Chen Helen H W, Song Im-Sook, Savaraj Niramol, Ishikawa Toshihisa
Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Cancer Metastasis Rev. 2007 Mar;26(1):71-83. doi: 10.1007/s10555-007-9045-3.
Platinum-based antitumor agents have been effective in the treatments of many human malignancies but the ultimate success of these agents is often compromised by development of drug resistance. One mechanism associated with resistance to platinum drugs is reduced intracellular accumulation owing to impaired drug intake, enhanced outward transport, or both. Mechanisms for transporting platinum drugs were not known until recent demonstrations that import and export transporters involved in maintenance copper homeostasis are also involved in the transport of these drugs. Ctr1, the major copper influx transporter, has been convincingly demonstrated to transport cisplatin and its analogues, carboplatin, and oxaliplatin. Evidence also suggests that the two copper efflux transporters ATP7A and ATP7B regulate the efflux of cisplatin. These observations are intriguing, because conventional thinking of the inorganic physiologic chemistry of cisplatin and copper is quite different. Hence, understanding the underlying mechanistic aspects of these transporters is critically important. While the mechanisms by which hCtr1, ATP7A and ATP7B transport copper ions have been studied extensively, very little is known about the mechanisms by which these transporters shuffle platinum-based antitumor agents. This review discusses the identification of copper transporters as platinum drug transporters, the structural-functional and mechanistic aspects of these transporters, the mechanisms that regulate their expression, and future research directions that may eventually lead to improved efficacy of platinum-based-based drugs in cancer chemotherapy through modulation of their transporters' activities.
铂类抗肿瘤药物在多种人类恶性肿瘤的治疗中已显示出疗效，但这些药物的最终成功往往因耐药性的产生而受到影响。与铂类药物耐药相关的一种机制是由于药物摄取受损、外向转运增强或两者兼而有之导致细胞内积累减少。直到最近有证据表明参与维持铜稳态的输入和输出转运蛋白也参与这些药物的转运，铂类药物的转运机制才为人所知。主要的铜流入转运蛋白Ctr1已被确凿证明可转运顺铂及其类似物卡铂和奥沙利铂。证据还表明，两种铜流出转运蛋白ATP7A和ATP7B调节顺铂的流出。这些观察结果很有趣，因为顺铂和铜的无机生理化学的传统观点有很大不同。因此，了解这些转运蛋白的潜在机制非常重要。虽然对hCtr1、ATP7A和ATP7B转运铜离子的机制已进行了广泛研究，但对于这些转运蛋白转运铂类抗肿瘤药物的机制却知之甚少。本综述讨论了铜转运蛋白作为铂类药物转运蛋白的鉴定、这些转运蛋白的结构功能和机制方面、调节其表达的机制，以及未来的研究方向，这些研究方向最终可能通过调节转运蛋白的活性来提高铂类药物在癌症化疗中的疗效。
