Abstract
Abstract The clinical use of platinum (Pt) agents is often compromised by the occurrence of drug resistance. Studies have shown reduced intracellular Pt accumulation in cells resistant to Pt drugs. Copper transporters have been reported to have a role in Pt influx and efflux. While the first member of this family, CTR1, has been shown to transport Pt, the role of the structurally similar CTR2 in Pt transport is unclear. The aim of this study was to assess the role of CTR2 in Pt based drug-transport using KB-3.1 cervical carcinoma cells and its cisplatin (KB-CP20) or oxaliplatin (KB-OX60) resistant subclones. In previous studies we reported that compared to parental cells the resistant cell lines have lower levels of intracellular Pt following cisplatin (CIS) or oxaliplatin (OX) exposure. We transfected parental KB-3.1 cells and its drug resistant sublines with CTR1, CTR2 or both transporters, and incubated cells with either CIS or OX. Intracellular Pt accumulation was not increased in any of the transfected parental KB-3.1 cells. In contrast, KB-CP20 cells transfected with CTR1, CTR2 or both trasnporters accumulated more CIS but not more OX compared to non-transfected KB-CP20 cells; while transfected KB-OX60 cells accumulated higher levels of both CIS and OX compared to non-transfected KB-OX 60 cells. In both resistant cell lines, the increased intracellular Pt observed after transtfection of the transporters was accompanied by increased DNA platination. Given the clinical utility of OX in colon carcinoma we next determined intracellular CIS and OX levels, the expression of proteins involved in copper transport (ATP7A, ATP7B, CTR1 and CTR2), and the IC50 for CIS and OX of six colon carcinoma cell lines. We found an inverse correlation between intracellular Pt levels and the IC50 of both drugs, and correlations between: (1) the IC50 of CIS and expression levels of CTR1, (2) intracellular CIS levels and expression levels of ATP7A, (3) expression levels of ATP7B and CTR2, and (4) OX accumulation and expression levels of ATP7A. In summary, we have shown CTR2 is able to transport Pt-containing drugs and increases intracellular Pt accumulation that is accompanied by greater DNA-platination. In unselected colon cancer cells, we have shown that the IC50 of a Pt based drug is determined by the intracellular accumulation of that drug, and to varying extent by the expression of copper transporters. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2554.
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