WFRF:(Larsson Mårten)
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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
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- Blom, Kristin (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Senkowski, Wojciech (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Jarvius, Malin (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- 2017-05-04
- 2017
- English.
- In: Immunopharmacology and immunotoxicology. - : Informa UK Limited. - 0892-3973 .- 1532-2513. ; 39:4, s. 199-210
- Journal article (peer-reviewed)
Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- Repositioning
- cancer therapy
- monocytes
- macrophages
- mebendazole
Publication and Content Type
- ref (subject category)
- art (subject category)
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- Andersson, Claes
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- Fryknäs, Mårten
- Nygren, Peter
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