Niclosamide and its analogs are potent inhibitors of Wnt/ß- catenin, mTOR and STAT3 signaling in ovarian cancer

Rebecca C. Arend, Angelina I. Londoño-Joshi, Abhishek Gangrade, Ashwini A. Katre, Chandrika Kurpad, Yonghe Li, Rajeev S. Samant, Pui Kai Li, Charles N. Landen, Eddy S. Yang, Bertha Hidalgo, Ronald D. Alvarez, John Michael Straughn, Andres Forero, Donald J. Buchsbaum

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

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/ß-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/ß-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.

Original languageEnglish
Pages (from-to)86803-86815
Number of pages13
JournalOncotarget
Volume7
Issue number52
StatePublished - 2016

Bibliographical note

Funding Information:
We are grateful to all our funding support and for the contributions of all the authors to the development of this manuscript. NIH grant support in the Comprehensive Flow Cytometry Core (CFCC) (P30 AR48311), Dr. Londono is funded by a NIH Research Training Program in Basic and Translation Oncology T32 Grant (T32CA183926). Dr. Arend is supported by the Foundation for Women's Cancer (WeRoc/OChO Ovarian Cancer Research Grant), Norma Livingston Foundation, AAOGF/ABOG Career Development Award. Dr. Hidalgo is supported by the NHLBI Diversity Supplement (HHSN268201300001) and a grant from the Robert Wood Johnson Foundation, New Connections Program.

Keywords

  • Cancer stem cells
  • Chemoresistance
  • Ovarian cancer
  • Targeted therapy
  • Wnt pathway

ASJC Scopus subject areas

  • Oncology

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