The Antihelmintic Drug Pyrvinium Pamoate Targets Aggressive Breast Cancer

Wei Xu,Darren Orton,Wendy A Woodward,Bisrat G Debeb,Ethan Lee,Rachel L Atkinson,Naoto T Ueno,Travis N Solley,Ann H Klopp,James M Reuben,Li Li,Lara Lacerda,Savitri Krishnamurthy,John S Mcmurray,Brian I Hang,Ming Tan

doi:10.1371/journal.pone.0071508

Abstract

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.

Highlights

Of the cells that make up a tumor’s bulk, a small population is purported to consist of tumor initiation cells (TICs), which have self-renewing and multipotent properties that lead to treatment resistance and recurrence
Accumulating evidence suggests that cells bearing functional and cell surface markers that correlate to tumor initiation are regulated by developmental pathways that are critical to normal stem cell survival, including Sonic hedgehog signaling [1], Notch signaling [2,3,4], and WNT signaling [5,6]
pyrvinium pamoate (PP) inhibited WNT signaling To confirm this activity in breast cancer cell lines, we examined whether b-catenin and non-phosphorylated b-catenin are downregulated by PP in human breast cancer cells

Summary

Introduction

Of the cells that make up a tumor’s bulk, a small population is purported to consist of tumor initiation cells (TICs), which have self-renewing and multipotent properties that lead to treatment resistance and recurrence. Accumulating evidence suggests that cells bearing functional and cell surface markers that correlate to tumor initiation are regulated by developmental pathways that are critical to normal stem cell survival, including Sonic hedgehog signaling [1], Notch signaling [2,3,4], and WNT signaling [5,6]. These pathways are attractive targets for potentially eliminating the TIC subpopulation. Considering the signaling pathway similarity between cancer stem cells and normal stem cells [23], it is not surprising that the WNT signaling pathway plays a key role in the self-renewal of breast cancer TICs [6,24]

Methods

Results

Conclusion