Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer
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Rebecca C. Arend1, Angelina I. Londoño-Joshi2, Abhishek Gangrade2, Ashwini A. Katre2, Chandrika Kurpad2, Yonghe Li3, Rajeev S. Samant4, Pui-Kai Li5, Charles N. Landen6, Eddy S. Yang2, Bertha Hidalgo7, Ronald D. Alvarez1, John Michael Straughn1, Andres Forero8, Donald J. Buchsbaum2
1University of Alabama at Birmingham, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Birmingham, AL, USA
2University of Alabama at Birmingham, Department of Radiation Oncology, Birmingham, AL, USA
3Southern Research Institute, Department of Oncology, Birmingham, AL, USA
4University of Alabama at Birmingham, Department of Pathology, Division of Molecular & Cellular Pathology, Birmingham, AL, USA
5Ohio State University, Department of Medicinal Chemistry and Pharmacognosy, Columbus, OH, USA
6University of Virginia, Department of Oncology, Division of Gynecologic Oncology, Charlottesville, VA, USA
7University of Alabama at Birmingham, Department of Epidemiology, Birmingham, AL, USA
8University of Alabama at Birmingham, Department of Medicine, Division of Hematology & Oncology, Birmingham, AL, USA
Rebecca C. Arend, email: [email protected]
Keywords: ovarian cancer, chemoresistance, cancer stem cells, targeted therapy, Wnt pathway
Received: June 01, 2016 Accepted: October 29, 2016 Published: November 19, 2016
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.
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