title: Sinapine as an active compound for inhibiting the proliferation of Caco-2 cells via downregulation of P-glycoprotein.
abstract: Sinapine, an alkaloid from seeds of the cruciferous species, shows favorable biological activities such as antioxidant and radio-protective activities. However, the inhibitory effect of sinapine on tumors, and the molecular mechanisms have not been completely understood thus far. In this study, we determined anti-proliferative effects of sinapine. We examined the anti-tumor effects of the combination of sinapine and doxorubicin. The results of the MTT assay and apoptosis showed that sinapine increased the sensitivity of Caco-2 cells to doxorubicin in a dose-dependent manner, whereas no or less effect was observed in the cells treated with doxorubicin alone. The combination of sinapine and doxorubicin had a synergistic effect and increased the cytotoxicity of doxorubicin against Caco-2 cells. Doxorubicin accumulation assay showed that sinapine increased the intracellular accumulation of doxorubicin in dose-dependent manner. Immunoblotting and QT-PCR analysis showed that sinapine suppressed P-glycoprotein (P-gp) expression via ubiquitination. A significant correlation was observed between the expression of p-ERK1/2 and P-gp. These results indicated that sinapine played an important role in the down-regulation of P-gp expression through suppression of FGFR4-FRS2α-ERK1/2 signaling pathway. To our knowledge, this is the first study to show that sinapine can be used as an effective natural compound for chemo-resistance.
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Center for Translational Medicine, The First Affiliated Hospital, College of Medicine, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: An
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Liuxin
authors.initials: L
authors.lastname: Feng
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Sicen
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Xi'an Jiaotong University, Xi'an, China. Electronic address: taozhang@mail.xjtu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects*; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; C005685:sinapine; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4; D002794:Choline
keywords: Caco-2; ERK1/2; FGFR4; P-glycoprotein; Sinapine; p-FRS2α