The Overlapping Transport Mechanism for cDDP and Copper

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, upregulating 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 Culowering agents through enhanced hCtr1 expression by upregulation 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. Platinum (Pt)-based antitumor drugs are the mainstay of chemotherapy for many types of human malignancies. These agents have been the dominant chemotherapeutic drugs for testicular and ovarian cancer during the past three decades (1). It has been well-recognized that DNA is the principal cellular lethal target of cisplatin (cDDP) by forming DNAPt crosslink adducts (2). For cDDP to reach its target, it has to travel through the cell membrane, cytoplasmic compartments, and enter the nucleus. Excess Pt drug is eliminated from the cells. While it is conceivable that each step along the way can give rise to drug resistance, it has been demonstrated that the amount of total cellular Pt content is proportional to the extent to which DNA-Pt adduct is formed, which in turn is correlated with treatment outcomes in patients using Pt drugs (3). These findings demonstrate that mechanisms underlying Pt drug transport (both import and export) and retention in the tumor cells are important determinants for the overall treatment activities. The Overlapping Transport Mechanism for cDDP and Copper Mechanisms of Pt drug transport are multifactorial. Early work on the field suggested that cDDP may enter the cells by means of passive diffusion (2). Many later studies demonstrated that cDDP utilizes the high-affinity copper (Cu) transporter-1 (Ctr1) to import drugσ into the cells (2, 4, 5). Ctr1 is the major Cu transporter in eukaryotic cells. Once Cu is inside the cells, it is delivered to various subcellular compartments by means of Cu chaperons, such as Atox1 which delivers Cu to the Golgi apparatus where Cu exporters, ATP7A and ATP7B, eliminate excess Cu. cDDP is 4157 This article is freely accessible online. Correspondence to: Macus Tien Kuo, Ph.D., Department of Translational Molecular Pathology (Unit 951), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. Tel: +1 7138346038, Fax: +1 7138346082, e-mail: [email protected]