Abstract:
The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs.
摘要:
含铂(Pt)的抗肿瘤药物,包括顺铂(顺式-二氨基二氯铂II,cDDP),卡铂,还有奥沙利铂,一直是癌症化疗的支柱。这些药物可有效治疗许多人类恶性肿瘤。Pt药物的主要细胞杀伤靶标是DNA。最近的发现强调了铂药物转运系统在癌症治疗中的重要作用。虽然已经提出了许多用于Pt-药物转运的机制,高亲和力铜转运蛋白(hCtr1),Cu伴侣(Atox1),和铜出口商(ATP7A和ATP7B)也参与cDDP运输,强调基于铂的癌症治疗中的铜稳态调节。结果表明,通过铜螯合剂降低细胞铜的生物可利用水平,hCtr1被转录因子Sp1转录上调,其结合Sp1和hCtr1的启动子。相比之下,Cu毒物Sp1升高,导致hCtr1和Sp1受到抑制,构成Cu-Sp1-hCtr1相互调节环。已经进行了在卡铂治疗中使用铜螯合剂(曲恩汀)的临床研究,以克服部分由于转运缺陷引起的Pt耐药性。虽然结果令人鼓舞,未来的发展可能包括靶向铜转运系统的多个步骤,以提高铂基癌症化疗的疗效。这篇综述的重点是描述Cu稳态调节与Pt药物抗肿瘤功效之间的机制相互关系。