The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer.
WNT signaling plays a key role in the self-renewal of tumor initiation cells (TICs). In this study, we used pyrvinium pamoate (PP), an FDA-approved antihelmintic drug that inhibits WNT signaling, to test whether pharmacologic inhibition of WNT signaling can specifically target TICs of aggressive bre...
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doaj-7271058255d14c78842fbbe8ff1956f32020-11-25T01:46:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0188e7150810.1371/journal.pone.0071508The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer.Wei XuLara LacerdaBisrat G DebebRachel L AtkinsonTravis N SolleyLi LiDarren OrtonJohn S McMurrayBrian I HangEthan LeeAnn H KloppNaoto T UenoJames M ReubenSavitri KrishnamurthyWendy A WoodwardWNT signaling plays a key role in the self-renewal of tumor initiation cells (TICs). In this study, we used pyrvinium pamoate (PP), an FDA-approved antihelmintic drug that inhibits WNT signaling, to test whether pharmacologic inhibition of WNT signaling can specifically target TICs of aggressive breast cancer cells. SUM-149, an inflammatory breast cancer cell line, and SUM-159, a metaplastic basal-type breast cancer cell line, were used in these studies. We found that PP inhibited primary and secondary mammosphere formation of cancer cells at nanomolar concentrations, at least 10 times less than the dose needed to have a toxic effect on cancer cells. A comparable mammosphere formation IC50 dose to that observed in cancer cell lines was obtained using malignant pleural effusion samples from patients with IBC. A decrease in activity of the TIC surrogate aldehyde dehydrogenase was observed in PP-treated cells, and inhibition of WNT signaling by PP was associated with down-regulation of a panel of markers associated with epithelial-mesenchymal transition. In vivo, intratumoral injection was associated with tumor necrosis, and intraperitoneal injection into mice with tumor xenografts caused significant tumor growth delay and a trend toward decreased lung metastasis. In in vitro mammosphere-based and monolayer-based clonogenic assays, we found that PP radiosensitized cells in monolayer culture but not mammosphere culture. These findings suggest WNT signaling inhibition may be a feasible strategy for targeting aggressive breast cancer. Investigation and modification of the bioavailability and toxicity profile of systemic PP are warranted.http://europepmc.org/articles/PMC3754994?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wei Xu Lara Lacerda Bisrat G Debeb Rachel L Atkinson Travis N Solley Li Li Darren Orton John S McMurray Brian I Hang Ethan Lee Ann H Klopp Naoto T Ueno James M Reuben Savitri Krishnamurthy Wendy A Woodward |
spellingShingle |
Wei Xu Lara Lacerda Bisrat G Debeb Rachel L Atkinson Travis N Solley Li Li Darren Orton John S McMurray Brian I Hang Ethan Lee Ann H Klopp Naoto T Ueno James M Reuben Savitri Krishnamurthy Wendy A Woodward The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer. PLoS ONE |
author_facet |
Wei Xu Lara Lacerda Bisrat G Debeb Rachel L Atkinson Travis N Solley Li Li Darren Orton John S McMurray Brian I Hang Ethan Lee Ann H Klopp Naoto T Ueno James M Reuben Savitri Krishnamurthy Wendy A Woodward |
author_sort |
Wei Xu |
title |
The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer. |
title_short |
The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer. |
title_full |
The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer. |
title_fullStr |
The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer. |
title_full_unstemmed |
The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer. |
title_sort |
antihelmintic drug pyrvinium pamoate targets aggressive breast cancer. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
WNT signaling plays a key role in the self-renewal of tumor initiation cells (TICs). In this study, we used pyrvinium pamoate (PP), an FDA-approved antihelmintic drug that inhibits WNT signaling, to test whether pharmacologic inhibition of WNT signaling can specifically target TICs of aggressive breast cancer cells. SUM-149, an inflammatory breast cancer cell line, and SUM-159, a metaplastic basal-type breast cancer cell line, were used in these studies. We found that PP inhibited primary and secondary mammosphere formation of cancer cells at nanomolar concentrations, at least 10 times less than the dose needed to have a toxic effect on cancer cells. A comparable mammosphere formation IC50 dose to that observed in cancer cell lines was obtained using malignant pleural effusion samples from patients with IBC. A decrease in activity of the TIC surrogate aldehyde dehydrogenase was observed in PP-treated cells, and inhibition of WNT signaling by PP was associated with down-regulation of a panel of markers associated with epithelial-mesenchymal transition. In vivo, intratumoral injection was associated with tumor necrosis, and intraperitoneal injection into mice with tumor xenografts caused significant tumor growth delay and a trend toward decreased lung metastasis. In in vitro mammosphere-based and monolayer-based clonogenic assays, we found that PP radiosensitized cells in monolayer culture but not mammosphere culture. These findings suggest WNT signaling inhibition may be a feasible strategy for targeting aggressive breast cancer. Investigation and modification of the bioavailability and toxicity profile of systemic PP are warranted. |
url |
http://europepmc.org/articles/PMC3754994?pdf=render |
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