Cytotoxic Effect of Disulfiram/Copper On Human Cervical Cancer Cell Lines and LGR5-Positive Cancer Stem-Like Cells

Abstract

Background: Tumor resistance is a global challenge for tumor treatment. Cancer stem cells (CSCs) are the main population of tumor cells for drug resistance. We have reported that high aldehyde dehydrogenase (ALDH) activity represents a functional marker for cervical CSCs. Here we aim at disulfiram (DS), an ALDH inhibitor, that has the potential as a novel treatment to be used for cervical cancer.Methods: MTT assay, western blot, FCS analysis and sorting, vector construction and transfection, in vivo anti-tumor assays were performed using cervical cancer cell lines SiHa and HeLa. Cell cycle distribution and cell apoptosis were carried out by flow cytometry. The cytotoxicity of DS was detected by MTT assay and a xenograft cervical cancer model. Results: Disulfiram was cytotoxic to cervical cancer cell lines in a copper (Cu)-dependent manner. Disulfiram/copper (DS/Cu) complex induced deregulation of S-phase and inhibited the expression of stemness marker in cervical cancer cells. DS/Cu caused the death of LGR5-positive cervical cancer cells, a cancer stem-like cell population, which lead to cisplatin resistance in cervical cancer cells. Furthermore, DS/Cu complex had the greater antitumor efficacy on cervical cancer than cisplatin group in vitro and in vivo. Conclusion: Our findings indicate that the cytotoxicity of DS/Cu complex may be superior to cisplatin because of targeting LGR5-positive cervical cancer stem-like cells in cervical cancer. Thus, the DS/Cu complex may represent a potential therapeutic strategy for cervical cancer patients.