Abstract
The copper transporter 1 (CTR1) is the major copper (Cu) influx transporter and also mediates the initial uptake of cisplatin (DDP), carboplatin (CBDCA) and oxaliplatin (L-OHP). Deletion of the gene coding for CTR1 in yeast or mouse embryonic fibroblasts substantially reduces the initial influx of all three Pt-containing drugs and renders them resistant to their cytotoxic effects. Forced over-expression of human CTR1 in the human A2780 ovarian carcinoma cells increases the uptake of DDP but appears to misdirect its distribution within the cell. DDP triggers rapid degradation of CTR1, thus reducing the level of its own influx transporter. This effect is reduced by drugs that block endocytosis or the proteosome. While CTR1 transports Cu through a pore that it forms in the plasma membrane, it transports DDP via quite a different mechanism that depends on endocytosis.
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Acknowledgments
This work was supported by the NIH grant CA 095298 and a grant from the Clayton Foundation for Medical Research. The production of 64Cu at Washington University School of Medicine was supported by the National Cancer Institute grant R24-CA86307.
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Howell, S.B., Safaei, R. (2009). CTR1 as a Determinant of Platinum Drug Transport. In: Bonetti, A., Leone, R., Muggia, F.M., Howell, S.B. (eds) Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-459-3_12
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