Salinomycin reduces growth, proliferation and metastasis of cisplatin resistant breast cancer cells via NF-kB deregulation

Abstract

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 (MCF7^DDP) 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 MCF7^DDP 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.

Keywords: BCL-2; CDDP resistant cancer cells; Combination therapy; NF-κB inhibitor; Salinomycin; Survivin; XIAP.