title: Emodin as an effective agent in targeting cancer stem-like side population cells of gallbladder carcinoma.
abstract: Side population (SP) cells are previously identified from bone marrow based on their capacity to efflux of the fluorescent dye Hoechst 33342. Recent studies demonstrate that SP cells isolated from various cancer cell lines and primary tumors possess stem-cell-like properties. Thus, targeting tumor SP cells may provide new strategies for treatment in clinic. We previously showed that 1,3,8-trihydroxy-6-methylanthraquinone (emodin), a reactive oxygen species (ROS) generator, enhanced sensitivity of gallbladder cancer SGC-996 cells to cisplatin (CDDP) via generation of ROS and downregulation of multidrug-resistance-associated protein 1 (MRP1). To determine whether emodin also acts effectively on cancer stem cells of gallbladder carcinoma, we use SP cells as a model of cancer stem-cell-like cells. Here, we found that emodin, via ROS-related mechanism and suppressing the function of ATP-binding cassette super-family G member (ABCG2), which is known to be associated with Hoechst dye efflux activity of SP cells, not only reduced the ratio, inhibited clone formation, and eliminated sphere formation of SP cells effectively, but also promoted obviously the intracellular accumulation of doxorubicin, the main substrate of the efflux pump ABCG2. In addition, emodin could sensitize CDDP, via inhibition of expression of ABCG2, to overcome chemoresistance of SP cells. Importantly, similar to the experiment in vitro, emodin/CDDP co-treatment in vivo suppressed the tumor growth derived from SP cells through downregulating ABCG2 expression. Our results suggest that emodin is an effective agent targeting cancer stem-like SP cells of gallbladder carcinoma, either alone or acts as a chemotherapy enhancer.
authors.affiliation: Division of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xin-xing
authors.initials: XX
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Dong
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Hao-lu
authors.initials: HL
authors.lastname: Wang
authors.forename: Yu-ying
authors.initials: YY
authors.lastname: Chen
authors.forename: Gui-ying
authors.initials: GY
authors.lastname: Shi
authors.forename: Jing
authors.initials: J
authors.lastname: Yi
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods*; D004642:Emodin / Q000494:pharmacology*; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D004642:Emodin; D002945:Cisplatin