Previous work has shown that cisplatin (CDDP) becomes concentrated in lysosomes, and that acquired resistance to CDDP is associated with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma cells was compared with that in CDDP-resistant 2008/

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.

A small increase in ATP7A expression produced resistance to all three of the clinically available Pt drugs. Whereas increased expression of ATP7A reduced Cu accumulation, it did not reduce accumulation of the Pt drugs. Under conditions where Cu triggered ATP7A relocalization, the Pt drugs did not. Thus, although ATP7A is an important determinant of sensitivity to the Pt drugs, there are substantial differences between Cu and the Pt drugs with respect to how they interact with ATP7A and the mechanism by which ATP7A protects the cell.

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