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

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

doi:10.18632/oncotarget.13466

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.

Highlights

Epithelial ovarian cancer (EOC) was responsible for an estimated 14,000 deaths in the United States in 2015 making it the deadliest gynecologic malignancy [1]
We investigated the effects of niclosamide, analog 11, and analog 32 on ovarian cancer cells and found that niclosamide and its analogs inhibited the Wnt/β-catenin, mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription-3 (STAT3) pathways in chemoresistant ovarian cancer cell lines, in cells derived from a chemoresistant ovarian cancer patientderived xenograft (PDX model), and tumorspheres cultured from cells isolated from the ascites of patients with ovarian cancer
We found that niclosamide decreased the stem cell marker ALHD1A1 and the Wnt pathway surface receptor LRP6. In this current study we demonstrate that niclosamide targets the Wnt pathway, but it targets the mTOR and the STAT3 pathways and targets CD133+ cancer stem cells (CSCs) and chemoresistant cells isolated from a patient-derived xenograft (PDX) ovarian cancer model

Summary

Introduction

Epithelial ovarian cancer (EOC) was responsible for an estimated 14,000 deaths in the United States in 2015 making it the deadliest gynecologic malignancy [1]. The majority of patients with EOC become clinically disease-free after initial treatment, 75% of patients recur within 5 years. Developing more effective and durable treatments is a significant unmet medical need in this disease context. A subset of cells may survive first-line chemotherapy and be responsible for the development of clinically detectable recurrence. These cells may be cancer stem cells (CSCs) that are resistant to primary therapy and are responsible for the generation of progeny cancer cells [2]

Objectives

Methods

Results

Conclusion