Antitumor effects of disulfiram/copper complex in the poorly-differentiated nasopharyngeal carcinoma cells via activating ClC-3 chloride channel.

The enhancement of the anticancer activity by disulfiram (DSF) chelated with copper (DSF/Cu ²⁺ ) has been investigated recently, while the underlying molecular mechanisms still need to be fully elucidated. Chloride channel-3 (ClC-3) is over-expressed in a variety of cancers and involves multiple tumor biological events. However, whether the over-expression of ClC-3 in tumor cells affects the sensitivity of anti-tumor drugs remains unclear. Here, we showed that the involvement of ClC-3 chloride channel in the selective cytotoxicity of DSF/Cu ²⁺ in the poorly-differentiated nasopharyngeal carcinoma. The EC ₅₀ of DSF alone and DSF/Cu ²⁺ in activating the Cl ^- channel were 95.36 μM and 0.31 μM in the CNE-2Z cells, respectively. DSF/Cu ²⁺ exhibited a positive correlation between the induction of the Cl ^- currents and the inhibition of cell proliferation. DSF/Cu ²⁺ increased the ClC-3 protein expression and induced the cell apoptosis. Cl ^- channel blockers, NPPB and DIDS, and ClC-3 siRNA partially inhibited the cell apoptosis, and depleted the Cl ^- currents induced by DSF/Cu ²⁺ in CNE-2Z cells. However, these effects could not be observed in the normal nasopharyngeal epithelium NP69-SV40 T cells. In vivo, the transplanted human nasopharyngeal carcinoma tumors size in the DSF/Cu ²⁺ group decreased about 73.2% of those in the solvent control group. The chloride blockers partially inhibited the antitumor action of DSF/Cu ²⁺ . These data demonstrated that the selective cytotoxicity of DSF/Cu ²⁺ may relate to its selective activation of ClC-3 Cl ^- channel pathways in CNE-2Z cells. ClC-3 Cl ^- channel can be viewed as a new and promising target for the treatment of nasopharyngeal carcinoma.
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