Women with
triple-negative breast cancer have worse prognosis compared to other
breast cancer subtypes. Acquired drug resistance remains to be an important reason influencing
triple-negative breast cancer treatment efficacy. A prevailing theory postulates that the
cancer resistance and recurrence results from a subpopulation of
tumor cells with stemness program, which are often insensitive to cytotoxic drugs such as
cisplatin. Recent studies suggested that
niclosamide, an anti-helminthic drug, has potential therapeutic activities against
breast cancer stem cells, which prompts us to determine its roles on eliminating
cisplatin-resistant
cancer cells. Hence, we established a stable
cisplatin-resistant MDA-MB-231 cell line (231-CR) through continuously exposure to increasing concentrations of
cisplatin (5-20 μmol/l). Interestingly, 231-CR exhibited properties associated to epithelial-mesenchymal transition with enhanced invasion, preserved proliferation, increased mammosphere formation, and reduced apoptosis compared to naive MDA-MB-231 sensitive cells (231-CS). Importantly,
niclosamide or combination with
cisplatin inhibited both 231-CS and 231-CR cell proliferation in vitro. In addition,
niclosamide reversed the EMT phenotype of 231-CR by downregulation of snail and
vimentin. Mechanistically,
niclosamide treatment in combination with or without
cisplatin significantly inhibited Akt, ERK, and Src signaling pathways. In vivo study showed that
niclosamide or combination with
cisplatin could repress the growth of xenografts originated from either 231-CS or 231-CR cells, with prominent suppression of Ki67 expression. These findings suggested that
niclosamide might serve as a novel therapeutic strategy, either alone or in combination with
cisplatin, for
triple-negative breast cancer treatment, especially those resistant to
cisplatin.