Role of copper transporters in resistance to platinating agents

Copper transporters have been proposed to be involved in cellular import and export of platinating agents. Expression of the human copper transporter 1 (hCtr1) is thought to result in increased sensitivity to cisplatin, whereas expression of ATP7A and ATP7B are thought to be involved in resistance to cisplatin either by sequestering drug away from its targets (ATP7A) or by exporting the drug from the cell (ATP7B). In this study, we evaluated the sensitivity of cells expressing copper transporters to cisplatin, carboplatin and oxaliplatin. We also examined whether O ⁶-benzylguanine, a modulator of platinating agent cytotoxicity, enhanced sensitivity of cells with or without the transporters to cisplatin. Overexpression of hCtr1 in the HEK293 cell line did not result in increased sensitivity to cisplatin, either alone or following treatment with O ⁶-benzylguanine. In contrast, overexpression of ATP7A and ATP7B in Me32a fibroblasts resulted in increased resistance to cisplatin, but not to carboplatin or oxaliplatin. ATP7A-expressing cells (MeMNK) showed a significant enhancement of cisplatin cytotoxicity following O ⁶-benzylguanine treatment, but ATP7B-expressing cells (MeWND) did not. Notably, expression of either ATP7A or ATP7B did not result in a change in total cytoplasmic platinum levels following treatment with BG plus cisplatin. The mechanism of BG enhancement of cisplatin cytotoxicity is not likely through regulation of copper transporters.