Growth inhibition of ovarian tumor-initiating cells by niclosamide

Yi Te Yo, Ya W. Lin, Yu Chi Wang, Curt Balch, Rui Lan Huang, Michael W Y Chan, Huey Kang Sytwu, Chi Kuan Chen, Cheng Chang Chang, Kenneth P. Nephew, Tim Hui Ming Huang, Mu Hsien Yu, Hung-Cheng Lai

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy.

Original languageEnglish
Pages (from-to)1703-1712
Number of pages10
JournalMolecular Cancer Therapeutics
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 2012
Externally publishedYes

Fingerprint

Niclosamide
Neoplastic Stem Cells
Growth
Neoplasms
Ovarian Neoplasms
Pharmaceutical Preparations
Preclinical Drug Evaluations
Anthelmintics
Metabolic Networks and Pathways
Tumor Cell Line
Oxidation-Reduction
Coloring Agents
Stem Cells
Therapeutics
Cell Membrane
Phenotype
Gene Expression
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Growth inhibition of ovarian tumor-initiating cells by niclosamide. / Yo, Yi Te; Lin, Ya W.; Wang, Yu Chi; Balch, Curt; Huang, Rui Lan; Chan, Michael W Y; Sytwu, Huey Kang; Chen, Chi Kuan; Chang, Cheng Chang; Nephew, Kenneth P.; Huang, Tim Hui Ming; Yu, Mu Hsien; Lai, Hung-Cheng.

In: Molecular Cancer Therapeutics, Vol. 11, No. 8, 08.2012, p. 1703-1712.

Research output: Contribution to journalArticle

Yo, YT, Lin, YW, Wang, YC, Balch, C, Huang, RL, Chan, MWY, Sytwu, HK, Chen, CK, Chang, CC, Nephew, KP, Huang, THM, Yu, MH & Lai, H-C 2012, 'Growth inhibition of ovarian tumor-initiating cells by niclosamide', Molecular Cancer Therapeutics, vol. 11, no. 8, pp. 1703-1712. https://doi.org/10.1158/1535-7163.MCT-12-0002
Yo, Yi Te ; Lin, Ya W. ; Wang, Yu Chi ; Balch, Curt ; Huang, Rui Lan ; Chan, Michael W Y ; Sytwu, Huey Kang ; Chen, Chi Kuan ; Chang, Cheng Chang ; Nephew, Kenneth P. ; Huang, Tim Hui Ming ; Yu, Mu Hsien ; Lai, Hung-Cheng. / Growth inhibition of ovarian tumor-initiating cells by niclosamide. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 8. pp. 1703-1712.
@article{075f1494172e4faaba85a01bb39012c6,
title = "Growth inhibition of ovarian tumor-initiating cells by niclosamide",
abstract = "A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy.",
author = "Yo, {Yi Te} and Lin, {Ya W.} and Wang, {Yu Chi} and Curt Balch and Huang, {Rui Lan} and Chan, {Michael W Y} and Sytwu, {Huey Kang} and Chen, {Chi Kuan} and Chang, {Cheng Chang} and Nephew, {Kenneth P.} and Huang, {Tim Hui Ming} and Yu, {Mu Hsien} and Hung-Cheng Lai",
year = "2012",
month = "8",
doi = "10.1158/1535-7163.MCT-12-0002",
language = "English",
volume = "11",
pages = "1703--1712",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Growth inhibition of ovarian tumor-initiating cells by niclosamide

AU - Yo, Yi Te

AU - Lin, Ya W.

AU - Wang, Yu Chi

AU - Balch, Curt

AU - Huang, Rui Lan

AU - Chan, Michael W Y

AU - Sytwu, Huey Kang

AU - Chen, Chi Kuan

AU - Chang, Cheng Chang

AU - Nephew, Kenneth P.

AU - Huang, Tim Hui Ming

AU - Yu, Mu Hsien

AU - Lai, Hung-Cheng

PY - 2012/8

Y1 - 2012/8

N2 - A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy.

AB - A recent hypothesis for cancer chemoresistance posits that cytotoxic survival of a subpopulation of tumor progenitors drives the propagation of recurrent disease, underscoring the need for new therapeutics that target such primitive cells. To discover such novel compounds active against drug-resistant ovarian cancer, we identified a subset of chemoresistant ovarian tumor cells fulfilling current definitions of cancer-initiating cells from cell lines and patient tumors using multiple stemness phenotypes, including the expression of stem cell markers, membrane dye efflux, sphere formation, potent tumorigenicity, and serial tumor propagation. We then subjected such stem-like ovarian tumor-initiating cells (OTIC) to high-throughput drug screening using more than 1,200 clinically approved drugs. Of 61 potential compounds preliminarily identified, more stringent assessments showed that the antihelmintic niclosamide selectively targets OTICs in vitro and in vivo. Gene expression arrays following OTIC treatment revealed niclosamide to disrupt multiple metabolic pathways affecting biogenetics, biogenesis, and redox regulation. These studies support niclosamide as a promising therapy for ovarian cancer and warrant further preclinical and clinical evaluation of this safe, clinically proven drug for the management of this devastating gynecologic malignancy.

UR - http://www.scopus.com/inward/record.url?scp=84864874626&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864874626&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-12-0002

DO - 10.1158/1535-7163.MCT-12-0002

M3 - Article

VL - 11

SP - 1703

EP - 1712

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 8

ER -