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The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
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2017 (English)In: Immunopharmacology and immunotoxicology, ISSN 0892-3973, E-ISSN 1532-2513, Vol. 39, no 4, 199-210 p.Article in journal (Refereed) Published
Abstract [en]

Mebendazole (MBZ), a drug commonly used for helminitic infections, has recently gained substantial attention as a repositioning candidate for cancer treatment. However, the mechanism of action behind its anticancer activity remains unclear. To address this problem, we took advantage of the curated MBZ-induced gene expression signatures in the LINCS Connectivity Map (CMap) database. The analysis revealed strong negative correlation with MEK/ERK1/2 inhibitors. Moreover, several of the most upregulated genes in response to MBZ exposure were related to monocyte/macrophage activation. The MBZ-induced gene expression signature in the promyeloblastic HL-60 cell line was strongly enriched in genes involved in monocyte/macrophage pro-inflammatory (M1) activation. This was subsequently validated using MBZ-treated THP-1 monocytoid cells that demonstrated gene expression, surface markers and cytokine release characteristic of the M1 phenotype. At high concentrations MBZ substantially induced the release of IL-1 beta and this was further potentiated by lipopolysaccharide (LPS). At low MBZ concentrations, cotreatment with LPS was required for MBZ-stimulated IL-1 beta secretion to occur. Furthermore, we show that the activation of protein kinase C, ERK1/2 and NF-kappaB were required for MBZ-induced IL-1 release. MBZ-induced IL-1 release was found to be dependent on NLRP3 inflammasome activation and to involve TLR8 stimulation. Finally, MBZ induced tumor-suppressive effects in a coculture model with differentiated THP-1 macrophages and HT29 colon cancer cells. In summary, we report that MBZ induced a pro-inflammatory (M1) phenotype of monocytoid cells, which may, at least partly, explain MBZ's anticancer activity observed in animal tumor models and in the clinic.

Place, publisher, year, edition, pages
2017. Vol. 39, no 4, 199-210 p.
Keyword [en]
Repositioning, cancer therapy, monocytes, macrophages, mebendazole
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-329149DOI: 10.1080/08923973.2017.1320671ISI: 000403934300005PubMedID: 28472897OAI: oai:DiVA.org:uu-329149DiVA: diva2:1141761
Funder
Swedish Cancer Society
Available from: 2017-09-15 Created: 2017-09-15 Last updated: 2017-09-15Bibliographically approved

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Blom, KristinSenkowski, WojciechJarvius, MalinBerglund, MalinRubin, JennyLenhammar, LenaParrow, VendelaAndersson, ClaesLoskog, AngelicaFryknäs, MårtenNygren, PeterLarsson, Rolf

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Blom, KristinSenkowski, WojciechJarvius, MalinBerglund, MalinRubin, JennyLenhammar, LenaParrow, VendelaAndersson, ClaesLoskog, AngelicaFryknäs, MårtenNygren, PeterLarsson, Rolf
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Cancer Pharmacology and Computational MedicineScience for Life Laboratory, SciLifeLabExperimental and Clinical Oncology
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