title: Sinapine reverses multi-drug resistance in MCF-7/dox cancer cells by downregulating FGFR4/FRS2α-ERK1/2 pathway-mediated NF-κB activation.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We examined the effect of sinapine on reversal of chemoresistance in Michigan Cancer Foundation 7 (MCF-7)/dox breast cancer cells.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National-local Joint Engineering Research Center of Biodiagnostics & Biotherapy, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710004, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ding
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: taozhang@mail.xjtu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: anhongli@mail.xjtu.edu.cn.
authors.forename: Hongli
authors.initials: H
authors.lastname: An
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D016328:NF-kappa B; C005685:sinapine; D004317:Doxorubicin; D002794:Choline
keywords: Doxorubicin; FGFR4; MCF-7/dox; NF-κB; P-glycoprotein; Sinapine