title: Bazedoxifene as a Novel GP130 Inhibitor for Pancreatic Cancer Therapy.
abstract: The IL6/GP130/STAT3 pathway is crucial for tumorigenesis in multiple cancer types, including pancreatic cancer, and presents as a viable target for cancer therapy. We reported Bazedoxifene, which is approved as a selective estrogen modulator by FDA, as a novel inhibitor of IL6/GP130 protein-protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. STAT3 is one of the major downstream effectors of IL6/GP130. Here, we observed Bazedoxifene inhibited STAT3 phosphorylation and STAT3 DNA binding, induced apoptosis, and suppressed tumor growth in pancreatic cancer cells with persistent IL6/GP130/STAT3 signaling in vitro and in vivo In addition, IL6, but not INFγ, rescued Bazedoxifene-mediated reduction of cell viability. Bazedoxifene also inhibited STAT3 phosphorylation induced by IL6 and IL11, but not by OSM or STAT1 phosphorylation induced by INFγ in pancreatic cancer cells, suggesting that Bazedoxifene inhibits the GP130/STAT3 pathway mediated by IL6 and IL11. Furthermore, Bazedoxifene combined with paclitaxel or gemcitabine synergistically inhibited cell viability and cell migration in pancreatic cancer cells. These results indicate that Bazedoxifene is a potential agent and can generate synergism when combined with conventional chemotherapy in human pancreatic cancer cells and tumor xenograft in mice. Therefore, our results support that Bazedoxifene as a novel inhibitor of GP130 signaling and may be a potential and safe therapeutic agent for human pancreatic cancer therapy. Mol Cancer Ther; 15(11); 2609-19. ©2016 AACR.
authors.affiliation: Department of Pediatric Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.|Department of Pediatrics, Center for Childhood Cancer and Blood Diseases, the Research Institute at Nationwide Children's Hospital, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Center for Childhood Cancer and Blood Diseases, the Research Institute at Nationwide Children's Hospital, College of Medicine, The Ohio State University, Columbus, Ohio.|Department of Hematology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Pediatrics, Center for Childhood Cancer and Blood Diseases, the Research Institute at Nationwide Children's Hospital, College of Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland. jlin@som.umary.edu.
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D011485:Protein Binding; D050791:STAT Transcription Factors / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D016207:Cytokines; D007211:Indoles; D050791:STAT Transcription Factors; D020845:Selective Estrogen Receptor Modulators; D050822:Cytokine Receptor gp130; C447119:bazedoxifene