A Re-Evaluation of the Role of hCTR1, the Human High-Affinity Copper Transporter, in Platinum-Drug Entry into Human Cells

Abstract

Cisplatin (cDDP) is an anticancer drug used in a number of malignancies, including testicular, ovarian, cervical, bladder, lung, head, and neck cancers. Its use is limited by the development of resistance, often rationalized via effects on cellular uptake. It has been claimed that human copper transporter 1 (hCTR1), the human high-affinity copper transporter, is the major entry pathway for cDDP and related drugs via a mechanism that mimics copper. This is an unexpected property of hCTR1, a highly selective copper (I) transporter. We compared the uptake rates of copper with cDDP (and several analogs) into human embryonic kidney 293 cells overexpressing wildtype or mutant hCTR1, mouse embryonic fibroblasts that do or do not express CTR1, and human ovarian tumor cells that are sensitive or resistant to cDDP. We have also compared the effects of extracellular copper, which causes regulatory endocytosis of hCTR1, to those of cDDP. We confirm the correlation between higher hCTR1 levels and higher platinum drug uptake in tumor cells sensitive to the drug. However, we show that hCTR1 is not the major entry route of platinum drugs, and that the copper transporter is not internalized in response to extracellular drug. Our data suggest the major entry pathway for platinum drugs is not saturable at relevant concentrations and not protein-mediated. Clinical trials have been initiated that depend upon regulating membrane levels of hCTR1. If reduced drug uptake is a major factor in resistance, hCTR1 is unlikely to be a productive target in attempts to enhance efficacy, although the proteins involved in copper homeostasis may play a role.

Detection of Increased 64Cu Uptake by Human Copper Transporter 1 Gene Overexpression Using PET with 64CuCl2 in Human Breast Cancer Xenograft Model

“…However, Holzer et al reported that an enhanced expression of hCTR1 in ovarian cancer cells induced higher accumulation of CDDP and copper but only a marginal increase in the cytotoxicity of CDDP due to improper intracellular localization of CDDP (14). Therefore, the cytotoxicity induced by CTR1 expression and CDDP in cancer cells might still be controversial (28)(29)(30), and this issue should be resolved by performing a further study.…”

Third row transition metals for the treatment of cancer

“…Recently, much work has centred on the importance of copper transporters, such as CTR1, which can mediate uptake of cisplatin by yeast [4,5]. Although some evidence suggests that in human cells CTR1 can take up cisplatin and deliver it in a form that is capable of binding DNA and triggering apoptosis [6], iconoclastic data continue to emerge [7]. Other membrane proteins may also play a role in the uptake of platinum drugs and, in collaboration with the Giacomini laboratory, we showed that cells overexpressing the organic cation transporters OCT1 and OCT2 were significantly more sensitive to oxaliplatin than cisplatin [8].…”

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

“…In addition, survival with early stage NSCLC is also improved by chemotherapy following surgery (3). Chemotherapy may be administered alone or in combination with surgery or radiation therapy, and platinum-based anti-tumor agents, particularly cisplatin, have been widely used for the treatment of various human cancers, including NSCLC (4,5). These agents are initially effective in lung cancer patients, but due to the development of resistance and relapse in treated patients, the benefit of these platinum based compounds has been limited.…”