title: Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer.
abstract: Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of cancer stem cells (CSCs) include Wnt/β-catenin, mTOR, and STAT3. The major objective of our study was to investigate the treatment of ovarian cancer with targeted agents that inhibit these three pathways. Here we demonstrate that niclosamide, a salicylamide derivative, and two synthetically manufactured niclosamide analogs (analog 11 and 32) caused significant inhibition of proliferation of two chemoresistant ovarian cancer cell lines (A2780cp20 and SKOV3Trip2), tumorspheres isolated from the ascites of EOC patients, and cells from a chemoresistant patient-derived xenograft (PDX). This work shows that all three agents significantly decreased the expression of proteins in the Wnt/β-catenin, mTOR and STAT3 pathways and preferentially targeted cells that expressed the ovarian CSC surface protein CD133. It also illustrates the potential of drug repurposing for chemoresistant EOC and can serve as a basis for pathway-oriented in vivo studies.
authors.affiliation: University of Alabama at Birmingham, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Birmingham, AL, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Arend
authors.affiliation: University of Alabama at Birmingham, Department of Radiation Oncology, Birmingham, AL, USA.
authors.forename: Angelina I
authors.initials: AI
authors.lastname: Londoño-Joshi
authors.affiliation: University of Alabama at Birmingham, Department of Radiation Oncology, Birmingham, AL, USA.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Gangrade
authors.affiliation: University of Alabama at Birmingham, Department of Radiation Oncology, Birmingham, AL, USA.
authors.forename: Ashwini A
authors.initials: AA
authors.lastname: Katre
authors.affiliation: University of Alabama at Birmingham, Department of Radiation Oncology, Birmingham, AL, USA.
authors.forename: Chandrika
authors.initials: C
authors.lastname: Kurpad
authors.affiliation: Southern Research Institute, Department of Oncology, Birmingham, AL, USA.
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
authors.affiliation: University of Alabama at Birmingham, Department of Pathology, Division of Molecular & Cellular Pathology, Birmingham, AL, USA.
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Samant
authors.affiliation: Ohio State University, Department of Medicinal Chemistry and Pharmacognosy, Columbus, OH, USA.
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.affiliation: University of Virginia, Department of Oncology, Division of Gynecologic Oncology, Charlottesville, VA, USA.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
authors.affiliation: University of Alabama at Birmingham, Department of Radiation Oncology, Birmingham, AL, USA.
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
authors.affiliation: University of Alabama at Birmingham, Department of Epidemiology, Birmingham, AL, USA.
authors.forename: Bertha
authors.initials: B
authors.lastname: Hidalgo
authors.affiliation: University of Alabama at Birmingham, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Birmingham, AL, USA.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.affiliation: University of Alabama at Birmingham, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Birmingham, AL, USA.
authors.forename: John Michael
authors.initials: JM
authors.lastname: Straughn
authors.affiliation: University of Alabama at Birmingham, Department of Medicine, Division of Hematology & Oncology, Birmingham, AL, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.affiliation: University of Alabama at Birmingham, Department of Radiation Oncology, Birmingham, AL, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009534:Niclosamide / Q000031:analogs & derivatives / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D011506:Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D009534:Niclosamide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Wnt pathway; cancer stem cells; chemoresistance; ovarian cancer; targeted therapy