Abstract
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.
Highlights
Breast cancer has become one of the most common malignancies among the female population and its prevalence has increased in women ≤40 years of age [1]
To explore the inhibitory effect of DSF in vitro, we initially examined the cytotoxicity of DSF on three breast cancer cell lines by MTT assay
Since DSF is an irreversible inhibitor of Aldehyde dehydrogenase (ALDH) [24], and ALDH + stem-like cells may play a role in cisplatin resistance [25], we studied whether DSF combined with cisplatin could overcome cisplatin resistance
Summary
Breast cancer has become one of the most common malignancies among the female population and its prevalence has increased in women ≤40 years of age [1]. It accounts for 22.9% of all female cancers worldwide [2]. Cancer stem cells (CSCs) are thought to contribute to drug resistance and cancer recurrence as they are proliferative quiescent and self-renewing tumor cell populations. These cells have stem cell characteristics, and were first isolated in breast tumors in 2003 [3]. It would be promising to develop alternative adjuvant methods that could target self-renewing and resistant CSCs directly [8]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have