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

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

Radiation Medicine

Research output: Contribution to journal › Article › peer-review

60 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 language	English
Pages (from-to)	86803-86815
Number of pages	13
Journal	Oncotarget
Volume	7
Issue number	52
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Cite this

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title = "Niclosamide and its analogs are potent inhibitors of Wnt/{\ss}- 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/{\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.",

keywords = "Cancer stem cells, Chemoresistance, Ovarian cancer, Targeted therapy, Wnt pathway",

author = "Arend, {Rebecca C.} and Londo{\~n}o-Joshi, {Angelina I.} and Abhishek Gangrade and Katre, {Ashwini A.} and Chandrika Kurpad and Yonghe Li and Samant, {Rajeev S.} and Li, {Pui Kai} and Landen, {Charles N.} and Yang, {Eddy S.} and Bertha Hidalgo and Alvarez, {Ronald D.} and Straughn, {John Michael} and Andres Forero and Buchsbaum, {Donald J.}",

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.",

year = "2016",

language = "English",

volume = "7",

pages = "86803--86815",

number = "52",

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TY - JOUR

T1 - Niclosamide and its analogs are potent inhibitors of Wnt/ß- catenin, mTOR and STAT3 signaling in ovarian cancer

AU - Arend, Rebecca C.

AU - Londoño-Joshi, Angelina I.

AU - Gangrade, Abhishek

AU - Katre, Ashwini A.

AU - Kurpad, Chandrika

AU - Li, Yonghe

AU - Samant, Rajeev S.

AU - Li, Pui Kai

AU - Landen, Charles N.

AU - Yang, Eddy S.

AU - Hidalgo, Bertha

AU - Alvarez, Ronald D.

AU - Straughn, John Michael

AU - Forero, Andres

AU - Buchsbaum, Donald J.

N1 - 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.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Cancer stem cells

KW - Chemoresistance

KW - Ovarian cancer

KW - Targeted therapy

KW - Wnt pathway

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M3 - Article

C2 - 27888804

AN - SCOPUS:85007452262

SN - 1949-2553

VL - 7

SP - 86803

EP - 86815

JO - Oncotarget

JF - Oncotarget

IS - 52

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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