The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation

Blom, Kristin; Senkowski, Wojciech; Jarvius, Malin; Berglund, Malin; Rubin, Jenny; Lenhammar, Lena; Parrow, Vendela; Andersson, Claes; Loskog, Angelica; Fryknäs, Mårten; Nygren, Peter; Larsson, Rolf

doi:10.1080/08923973.2017.1320671

Cited by 23 publications

(35 citation statements)

References 42 publications

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“…Again, MBZ at 1-10 μM had little or no effect on cytokine release from non-activated PBMCs (Figure 3a ) but stimulated the release of several pro-inflammatory cytokines including TNFα, IL1β, IFNγ, IL6 from PBMCs activated by IL2 and anti-CD3 stimulation (Figure 3b ). This has clear resemblance with our previous study in which MBZ at low concentrations require priming with LPS to stimulate pro-inflammatory cytokine (primarily IL1β) release in the THP-1 model [ 18 ]. IL1β secretion is suggested to require two signals.…”

Section: Resultssupporting

confidence: 81%

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Mebendazole stimulates CD14+ myeloid cells to enhance T-cell activation and tumour cell killing

et al. 2018

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Mebendazole (MBZ) was recently shown to induce a tumor suppressive M1 phenotype in THP-1 monocytes and macrophages. In the present study the immune effects of MBZ was further investigated using human peripheral blood mononuclear cells (PBMCs) co-cultured with tumour cells. The Biomap platform was used to screen for biomarkers induced from MBZ exposed co-cultures of T-cell receptor activated PBMCs, HT29 colon cancer cells and either human fibroblasts or human umbilical vein endothelial cells (HUVEC) cells. In these co-culture systems MBZ at 0.3-10 μM induced significant increases in TNFα and IFNγ indicating immune stimulation. PBMC cultures alone were subsequently tested for activation status and only in PBMCs activated by CD3/IL2 stimulation and MBZ, at a clinically achievable concentration, was able to increase PBMC clustering and release of pro-inflammatory IFNγ, TNFα, IL6 and IL1β cytokines. Moreover, when PBMC cultures were functionally tested for immune cell killing of lung cancer A549NucLightRed cells, MBZ significantly increased tumour cell apoptosis and reduced the number of surviving tumour cells. This effect was dependent on the presence of CD14 monocytes/macrophages in the co-culture. In summary, MBZ potentiated the immune stimulatory and anticancer effects of anti-CD3/IL2 activated PBMCs which could be relevant to explain the anticancer activity of MBZ observed in the clinic.

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Section: Resultssupporting

confidence: 81%

“…Recently, we demonstrated that MBZ induce a pro-inflammatory tumour-suppressive M1 phenotype in THP-1 monocytes and macrophages. MBZ-induced IL1β release was found to be dependent on NLRP3 inflammasome activation and to involve toll-like receptor 8 (TLR8) stimulation [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Mebendazole stimulates CD14+ myeloid cells to enhance T-cell activation and tumour cell killing

et al. 2018

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“…Interestingly, others have demonstrated the induction of a more pro-inflammatory phenotype of macrophage using mebendazole. 24 , 25 In those experiments, mebendazole increased secretion of IL1b and TNF through activation of the ERK pathway. In our hands, ERK inhibition did not abrogate the macrophage-inducing effects of albendazole [data not shown].…”

Section: Discussionmentioning

confidence: 85%

Benzimidazoles Promote Anti-TNF Mediated Induction of Regulatory Macrophages and Enhance Therapeutic Efficacy in a Murine Model

Wildenberg

Levin

Ceroni

et al. 2017

Journal of Crohn's and Colitis

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Background and AimsRegulatory macrophages play a critical role in tissue repair, and we have previously shown that anti-tumour necrosis factor [TNF] antibodies induce these macrophages in vitro and in vivo in IBD patients. The induction of regulatory macrophages can be potentiated using the combination of anti-TNF and thiopurines, consistent with the enhanced efficacy of this combination therapy described in clinical trials. As thiopurines are unfortunately associated with significant side effects, we here aimed to identify alternatives for combination therapy with anti-TNF, using the macrophage induction model as a screening tool.MethodsMixed lymphocyte reactions were treated with anti-TNF and a library of 1600 drug compounds. Induction of CD14+CD206+ macrophages was analysed by flow cytometry. Positive hits were validated in vitro and in the T cell transfer model of colitis.ResultsAmong the 98 compounds potentiating the induction of regulatory macrophages by anti-TNF were six benzimidazoles, including albendazole. Albendazole treatment in the presence of anti-TNF resulted in alterations in the tubulin skeleton and signalling though AMPK, which was required for the enhanced induction. Combination therapy also increased expression levels of the immunoregulatory cytokine IL-10. In vivo, albendazole plus anti-TNF combination therapy was superior to monotherapy in a model of colitis, in terms of both induction of regulatory macrophages and improvement of clinical symptoms.ConclusionsAlbendazole enhances the induction of regulatory macrophages by anti-TNF and potentiates clinical efficacy in murine colitis. Given its favourable safety profile, these data indicate that the repurposing of albendazole may be a novel option for anti-TNF combination therapy in IBD.

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“…Its anti-cancer properties were notably demonstrated in gliomas [11,14,27] and there is currently 3 ongoing clinical trials in high-grade gliomas in both adult and pediatric patients (NCT01729260, NCT02644291 and NCT01837862). Furthermore, a recent phase I trial demonstrated that administration of MBZ concomitantly with radiotherapy and temozolomide chemotherapy was safe in high-grade glioma patients [28] Although multiple studies have highlighted different mechanisms of action of MBZ in cancer cells [12][13][14][15][16], including its effects on the microtubule network [8,11,14,17,18], its precise molecular target(s) in tumor cells remained to be ascertained. Herein, we used in silico target prediction to unveil novel therapeutic targets for MBZ in GBM.…”

Section: Discussionmentioning

confidence: 99%

“…Several mechanisms of action have been proposed to explain the anticancer properties of MBZ. These include tumor angiogenesis inhibition [12,13], targeting of critical pathways involved in cancer such as Hedgehog signaling [14] and stimulation of anticancer immune response [15,16]. Most of these effects have been linked to the ability of MBZ to induce microtubule depolymerization in cancer cells [8,11,17,18].…”

Section: Introductionmentioning

confidence: 99%

In silicomolecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

Ariey-Bonnet

Carrasco

Grand

et al. 2020

Preprint

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The concept of polypharmacology involves the interaction of drug molecules with multiple molecular targets. It provides a unique opportunity for the repurposing of already-approved drugs to target key factors involved in human diseases. Herein, we used an in silico target prediction algorithm to investigate the mechanism of action of mebendazole, an antihelminthic drug, currently repurposed in the treatment of brain tumors. First, we confirmed that mebendazole decreased the viability of glioblastoma cells in vitro. Our in silico approach unveiled 21 putative molecular targets for mebendazole, including 12 proteins significantly up-regulated at the gene level in glioblastoma as compared to normal brain tissue. Validation experiments were performed on three major kinases involved in cancer biology: ABL1, MAPK1/ERK2 and MAPK14/p38α. Mebendazole could inhibit the activity of these kinases in vitro in a dose-dependent manner, with a high potency against MAPK14. Its direct binding to MAPK14 was further validated in vitro and inhibition of MAPK14 kinase activity was confirmed in live glioblastoma cells. Consistent with biophysical data, molecular modeling suggested that mebendazole was able to bind to the catalytic site of MAPK14. Finally, gene silencing demonstrated that MAPK14 is involved in glioblastoma tumor spheroid growth and response to mebendazole treatment. This study thus highlighted the role of MAPK14 in the anticancer mechanism of action of mebendazole and provides further rationale for the pharmacological targeting of MAPK14 in brain tumors. It also opens new avenues for the development of novel MAPK14/p38α inhibitors to treat human diseases. Significance StatementThis study provides a framework to investigate drug polypharmacology by rapidly identifying novel molecular targets of already-approved drugs. It unveils a new mechanism involved in the anticancer activity of anti-helminthic drug, mebendazole, which is currently being repurposed for the treatment of brain tumors. By helping to decipher the mechanism(s) of action of repurposed drugs in their new indications, this approach could contribute to the development of safer and more effective therapeutic strategies in oncology and beyond.

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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

Cited by 23 publications

References 42 publications

Mebendazole stimulates CD14+ myeloid cells to enhance T-cell activation and tumour cell killing

Mebendazole stimulates CD14+ myeloid cells to enhance T-cell activation and tumour cell killing

Benzimidazoles Promote Anti-TNF Mediated Induction of Regulatory Macrophages and Enhance Therapeutic Efficacy in a Murine Model

In silicomolecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

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