Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Abstract

Multiple lines of evidence indicate that the platinum-containing cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis. The cytotoxicity of the platinum drugs is directly related to how much drug enters the cell, and almost all cells that have acquired resistance to the platinum drugs exhibit reduced drug accumulation. The major copper influx transporter, copper transporter 1 (CTR1), has now been shown to control the tumor cell accumulation and cytotoxic effect of cisplatin, carboplatin, and oxaliplatin. There is a good correlation between change in CTR1 expression and acquired cisplatin resistance among ovarian cancer cell lines, and genetic knockout of CTR1 renders cells resistant to cisplatin in vivo. The expression of CTR1 is regulated at the transcriptional level by copper via Sp1 and at the post-translational level by the proteosome. Copper and cisplatin both trigger the down-regulation of CTR1 via a process that involves ubiquitination and proteosomal degradation and requires the copper chaperone antioxidant protein 1 (ATOX1). The cisplatin-induced degradation of CTR1 can be blocked with the proteosome inhibitor bortezomib, and this increases the cellular uptake and the cytotoxicity of cisplatin in a synergistic manner. Copper and platinum(II) have similar sulfur binding characteristics, and the presence of stacked rings of methionines and cysteines in the CTR1 trimer suggest a mechanism by which CTR1 selectively transports copper and the platinum-containing drugs via sequential transchelation reactions similar to the manner in which copper is passed from ATOX1 to the copper efflux transporters.

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

“…Ctr1 controls copper uptake, while ATP7A and ATP7B control the copper export from cells (23)(24)(25). Previous studies have identified that copper ion transport proteins are closely associated with the development of cisplatin resistance (16,26,27). These copper transporters include Ctr1 and ATP7B and ATP7A (23,28), which together regulate the overall intracellular cisplatin levels.…”

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].…”

Interaction between the Anticancer Drug Cisplatin and the Copper Chaperone Atox1 in Human Melanoma Cells

“…It has been shown to play a major role in CisPt uptake and cytotoxicity [3]. The absence of Ctr1 render cells resistant to CisPt [4] whereas patients with high levels of Ctr1 in their tumors responded better to platinum drug treatment [5].…”