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Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at the Cellular Level

Combining the multikinase inhibitor sorafenib with the platinum-based chemotherapy of solid tumors was expected to improve treatment outcome. However, in many clinical trials, no benefit from sorafenib addition to the platinum-containing regimen could be demonstrated. Moreover, in some studies, decreased survival of ovarian cancer patients as well as non-small cell lung cancer patients with squamous cell histology was observed. The aim of this study was to investigate the cellular mechanisms of the pharmacological interaction between platinum drugs and sorafenib in different cancer cell lines. The interaction was characterized by combination index analysis, platinum accumulation and DNA platination were determined using flameless atomic absorption spectrometry, and protein expression was assessed with Western blot. In the sensitive A2780 ovarian carcinoma and H520 squamous cell lung carcinoma cell lines, sorafenib induced downregulation of Na+,K+-ATPase. In A2780 cells, the kinase inhibitor also decreased the expression of copper transporter 1 (CTR1). As a result, sorafenib treatment led to a diminished cellular accumulation of cisplatin and carboplatin and to a decrease in DNA platination in these cell lines. This was not the case in the cisplatin-resistant A2780cis ovarian carcinoma and H522 lung adenocarcinoma cell lines featuring lower basal expression of the above-mentioned transporters. In all cell lines studied, an antagonistic interaction between platinum drugs and sorafenib was found. Our results suggest that sorafenib impairs cisplatin and carboplatin uptake through downregulation of CTR1 and/or Na+,K+-ATPase resulting in reduction of DNA platination. This effect is not observed in cancer cells with defects in platinum accumulation.