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  • Title: Effect of copper and role of the copper transporters ATP7A and CTR1 in intracellular accumulation of cisplatin.
    Author: Matsumoto S, Tanaka T, Kurokawa H, Matsuno K, Hayashida Y, Takahashi T.
    Journal: Anticancer Res; 2007; 27(4B):2209-16. PubMed ID: 17695505.
    Abstract:
    An investigation was carried out as to whether copper affected the intracellular accumulation of cisplatin (cis-diamminedichloroplatinum(II); CDDP) and whether changes in the expression of ATP7A and CTR1 were related to acquired resistance using CDDP-sensitive (KB) and -resistant (KBR/0.8, KBR/1.2) cells. Intracellular platinum accumulation and platinum-DNA adducts were significantly lower in the CDDP-resistant sublines compared with KB cells. Treatment with 750 microM CuSO4 increased the amount of intracellular platinum 1.8-, 3.2-, and 3.9-fold in KB, KBR/0.8, and KBR/1.2 cells respectively, and increased the platinum-DNA adducts by 1.9-fold in KB cells and by 3.2-fold in KBR/1.2 cells. The level of ATP7A was greatly reduced and CTR1 expression slightly decreased in KBR/1.2 cells compared with KB cells. ATP7A expression was markedly increased by exposure to CDDP with or without copper in KB cells but not in KBR/1.2 cells. CDDP and copper did not increase the level of CTR1 in KB or KBR/1.2 cells. These results indicate that a high concentration of copper causes a significant increase in the cellular accumulation of CDDP and binding of platinum to DNA independently of CTR1 expression in KB cells and CDDP-resistant sublines thereof and that the acquisition of CDDP resistance is associated with a greatly reduced level of ATP7A and a marginally lower expression of CTR1.
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