Sinapine reverses multi-drug resistance in MCF-7/dox cancer cells by downregulating FGFR4/FRS2α-ERK1/2 pathway-mediated NF-κB activation

Sinapine, an alkaloid derived from seeds of the cruciferous species, shows favorable biological properties, such as antioxidant and radio-protective activities. The inhibitory effect of sinapine on acquired chemoresistance in tumor cells and the underlying molecular mechanisms remain unknown. We examined the effect of sinapine on reversal of chemoresistance in Michigan Cancer Foundation 7 (MCF-7)/dox breast cancer cells. Combination treatment with sinapine and doxorubicin synergistically increased the cytotoxicity of doxorubicin in MCF-7/dox cells, as shown using a cell apoptosis assay. An accumulation assay demonstrated that sinapine increased the intracellular concentration of doxorubicin in a dose-dependent manner. Immunoblotting and real time polymerase chain reaction (RT-PCR) analysis showed that sinapine downregulated multi-drug resistance 1 (MDR1) expression. A significant correlation was observed between the expression of MDR1, phospho-factor receptor substrate (FRS), phospho-extracellular signal regulated kinase (ERK)1/2, and nuclear factor kappa B (NF-κB). Chromatin immunoprecipitation (ChIP) assay indicated that sinapine inhibited binding of the transcription factor NF-κB to the MDR1 promoter. Our findings indicated that sinapine played an important role in the downregulation of MDR1 expression through suppression of fibroblast growth factor receptor (FGFR)4/FRS2α-ERK1/2 mediated NF-κB activation in MCF-7/dox cancer cells.