title: Effect of copper and role of the copper transporters ATP7A and CTR1 in intracellular accumulation of cisplatin.
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.
authors: Division of Oral and Maxillofacial Reconstructive Surgery, Department of Oral Diagnostic Science, Kyushu Dental College, 2-6-1 Manazuru, Kokura-kita-ku, Kitakyushu 803-8580, Japan.
authors: Shinobu
authors: S
authors: Matsumoto
authors: Toshiko
authors: T
authors: Tanaka
authors: Hideo
authors: H
authors: Kurokawa
authors: Koji
authors: K
authors: Matsuno
authors: Yutaka
authors: Y
authors: Hayashida
authors: Tetsu
authors: T
authors: Takahashi
mesh_terms: D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D027682:Cation Transport Proteins / Q000096:biosynthesis / Q000378:metabolism*; D002945:Cisplatin / Q000493:pharmacokinetics*; D019327:Copper Sulfate / Q000494:pharmacology*; D000079923:Copper Transporter 1; D000073840:Copper-Transporting ATPases; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007624:KB Cells
chemical_list: D000970:Antineoplastic Agents; D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D004273:DNA, Neoplasm; C490079:SLC31A1 protein, human; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D019327:Copper Sulfate; D002945:Cisplatin