Cisplatin (cis-diamminedichloro-
platinum, CDDP), is a widely used
platinum compound for various solid
tumors including
breast cancer as first line of
therapy. However, its positive effects are limited due to acquired drug resistance and severe side effects in non-malignant tissue, especially due to dose-dependent nephro- and/or neuro-toxicity.
Salinomycin is an
antibiotic with coccidiostat effect and has shown anticancer efficacy against various
cancer cells with selectivity in targeting cancer stem cells. In the present study, anticancer efficacy and mechanism of action of
salinomycin in CDDP-resistant human
breast cancer (MCF7DDP) cells has been examined. Initially, we generated CDDP-resistant cells by a new protocol followed by checking the anticancer efficacy of
salinomycin through MTT, clonogenic,
annexin-V/PI and sub-G1 assay. Our results demonstrated that
salinomycin diminished both cell proliferation and metastatic migration of MCF7DDP cells.
Salinomycin also induced
mitochondrial dysfunction in CDDP-resistant
breast cancer cells. The analysis of nuclear translocation of pro-survival
transcription factors by western blotting showed a distinct role of p65 (NF-κB) in CDDP-mediated resistance in
breast cancer.
Salinomycin abrogated nuclear translocation of NF-κB
proteins and also caused a concurrent reduction in NF-κB regulated expression of pro-survival
proteins e.g.,
survivin, XIAP and BCL-2 in CDDP-resistant cells. These results suggest that a follow up treatment of
salinomycin may be promising strategy against CDDP resistant
breast cancer cells and
metastasis and help in reducing CDDP-induced side effects.