The chemotherapeutic agent
cisplatin typically induces apoptosis by inhibiting the cell cycle. Cancer Stem Cells (CSCs), which are a proliferative quiescent and slowly-cycling cell population, are less sensitive and therefore frequently spared from toxic effects. Thus, it remains a priority to increase the sensitivity of CSCs to
cisplatin-based
chemotherapy, or to specifically target CSCs to improve the therapeutic outcome in
breast cancer.
Disulfiram (DSF) is a
drug used clinically for
alcoholism treatment that has displayed promising anti-
cancer activity in vitro and in
cancer xenografts in
breast cancer. Our study provides evidence that DSF inhibits
Aldehyde dehydrogenase (ALDH)
enzyme activity, inhibits the expression of stemness-related
transcription factors (Sox, Nanog, Oct) in CSC derived from
breast cancer cell lines, and modulates intracellular
reactive oxygen species (ROS) generation. Importantly, our research proved that ALDH + stem-like cells play important roles in the resistance to the conventional chemotherapeutic agent
cisplatin. DSF enhances the cytotoxic effect of
cisplatin through inhibiting the stemness and by overcoming
cisplatin resistance of ALDH + stem-like cells. A quantitative measurement showed the synergistic effect of DSF and
cisplatin. Further, we show that ALDH + cancer stem-like cells and ALDH- bulk
cancer cells have different intrinsic ROS levels, what may explain differences in susceptibility to
cisplatin treatment. Importantly, this difference is eliminated by DSF treatment making both cell types similarly susceptible for cytotoxic effects by
cisplatin. These findings may influence chemotherapeutic treatment approaches in the future.