title: The antihelmintic drug pyrvinium pamoate targets aggressive breast cancer.
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.
authors.affiliation: Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Lara
authors.initials: L
authors.lastname: Lacerda
authors.forename: Bisrat G
authors.initials: BG
authors.lastname: Debeb
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Atkinson
authors.forename: Travis N
authors.initials: TN
authors.lastname: Solley
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Darren
authors.initials: D
authors.lastname: Orton
authors.forename: John S
authors.initials: JS
authors.lastname: McMurray
authors.forename: Brian I
authors.initials: BI
authors.lastname: Hang
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
authors.forename: Ann H
authors.initials: AH
authors.lastname: Klopp
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.forename: James M
authors.initials: JM
authors.lastname: Reuben
authors.forename: Savitri
authors.initials: S
authors.lastname: Krishnamurthy
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Woodward
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects; D011774:Pyrvinium Compounds / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000502:physiology; D060449:Wnt Signaling Pathway; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000871:Anthelmintics; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D011774:Pyrvinium Compounds; D011838:Radiation-Sensitizing Agents; D051176:beta Catenin; C024631:pyrvinium