The roles of copper transporters in cisplatin resistance

Abstract

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.

Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer

“…Thus, additional understanding of the underlying mechanism of platinum resistance may aid in the improvement of the effectiveness of platinum therapy and the response to platinum agents. Previous Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer studies have revealed that copper ions and platinum drugs may share the same transport system in the cell (12)(13)(14). A different study demonstrated that copper ion transport proteins not only participate in the metabolism of the copper ions, but also maintain the balance of copper and are ultimately associated with the development of cisplatin resistance (15).…”

“…A different study demonstrated that copper ion transport proteins not only participate in the metabolism of the copper ions, but also maintain the balance of copper and are ultimately associated with the development of cisplatin resistance (15). In particular, human copper transporter 1 (hCtr1) is the major copper influx transporter and also transports cisplatin and cisplatin analogues into cells (13), while two other copper transporters, consisting of copper-transporting p-type adenosine triphosphatase 1 (ATP7A) and 2 (ATP7B), regulate the efflux of cisplatin.…”

Hyperthermic potentiation of cisplatin by magnetic nanoparticle heaters is correlated with an increase in cell membrane fluidity

“…[5][6][7] Cis-diamminedichloroplatinum (II) (cDDP, cisplatin) is a well characterized chemotherapeutic agent that has shown promising results when combined with hyperthermia, but its mechanisms of potentiation remain largely unknown. 8,9 Uptake of cDDP by the cell appears to be mediated by two distinct mechanisms, ie, active transport via copper transporter receptors and passive diffusion through the cellular membrane. 10 Currently, it is believed that active transport is the dominant mechanism of cDDP uptake.…”

“…[14][15][16][17] Although some groups report distinct molecular behaviors of the different members of the hCTR family, which appear to be cell-dependent, all reports agree that copper, due to its affinity with the hCTR receptor, affects receptormediated entry of cDDP negatively, resulting in improved cytotoxicity. 9,[18][19][20][21][22][23] Although copper receptors have a critical role in the uptake of cisplatin, one of the first studies that focused on the mechanisms of thermal enhancement of cDDP reported an increase in cell membrane fluidity, which in turn augmented the uptake of cDDP. 17,24,25 Therefore, the synergism of cDDP and hyperthermic treatment can potentially be explained in the context of membrane fluidity.…”

Bim Protein Degradation Contributes to Cisplatin Resistance

“…There are many molecules and pathways that have been shown to contribute to cisplatin resistance (2)(3)(4)(5)(6)(7)(8)(9)(10). Deregulation of these proteins results in a variety of consequences, including insufficient DNA binding, increased DNA repair, and altered expression of genes involved in the cell death and survival pathways (9,11).…”