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

Rubin, Jenny; Mansoori, Sharmineh; Blom, Kristin; Berglund, Malin; Lenhammar, Lena; Andersson, Claes; Loskog, Angelica; Fryknäs, Mårten; Nygren, Peter; Larsson, Rolf

doi:10.18632/oncotarget.25713

Cited by 17 publications

(19 citation statements)

References 25 publications

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“…Mebendazole had little or no effect on clustering and cytokine release in non-activated PBMCs, but increased clustering and released proinflammatory cytokines, including TNF-α, IL-1β, IFN-γ, and IL-6 in CD3/IL2-activated PBMCs, potentiating both tumor cell reduction and apoptosis ( 91 ). Mebendazole induced a proinflammatory (M1) phenotype of monocytic cells (THP-1) via ERK1/2 and TLR8-dependent inflammasome activation ( 48 ).…”

Section: Antitumorigenic Effects Of Benzimidazole Anthelmintics In Camentioning

confidence: 99%

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

2020

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The development of refractory tumor cells limits therapeutic efficacy in cancer by activating mechanisms that promote cellular proliferation, migration, invasion, metastasis, and survival. Benzimidazole anthelmintics have broad-spectrum action to remove parasites both in human and veterinary medicine. In addition to being antiparasitic agents, benzimidazole anthelmintics are known to exert anticancer activities, such as the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, anti-angiogenesis, and blockage of glucose transport. These antitumorigenic effects even extend to cancer cells resistant to approved therapies and when in combination with conventional therapeutics, enhance anticancer efficacy and hold promise as adjuvants. Above all, these anthelmintics may offer a broad, safe spectrum to treat cancer, as demonstrated by their long history of use as antiparasitic agents. The present review summarizes central literature regarding the anticancer effects of benzimidazole anthelmintics, including albendazole, parbendazole, fenbendazole, mebendazole, oxibendazole, oxfendazole, ricobendazole, and flubendazole in cancer cell lines, animal tumor models, and clinical trials. This review provides valuable information on how to improve the quality of life in patients with cancers by increasing the treatment options and decreasing side effects from conventional therapy.

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Section: Antitumorigenic Effects Of Benzimidazole Anthelmintics In Camentioning

confidence: 99%

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

2020

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“…We speculate that MBZ may counteract these immune suppressive effects by restoring ERK activity. We have also previously shown that MBZ induces an M1 phenotype in human macrophage models and potentiates the anti-cancer activity of CD3/IL-2 activated peripheral blood mononuclear cells (PBMCs), the effect being attenuated by removal of CD14+ myeloid cells 38 .…”

Section: Discussionmentioning

confidence: 95%

Mebendazole is unique among tubulin-active drugs in activating the MEK–ERK pathway

Andersson

Selvin

Blom

et al. 2020

Sci Rep

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We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity in monocyte/macrophage models and induces eRK signalling. in the present study we investigated whether MBZ induced eRK activation is shared by other tubulin binding agents (tBAs) and if it is observable also in other human cell types. curated gene signatures for a panel of tBAs in the LincS connectivity Map (cMap) database showed a unique strong negative correlation of MBZ with MEK/ERK inhibitors indicating ERK activation also in non-haematological cell lines. L1000 gene expression signatures for MBZ treated THP-1 monocytes also connected negatively to MEK inhibitors. MeK/eRK phosphoprotein activity testing of a number of tBAs showed that only MBZ increased the activity in both THP-1 monocytes and PMA differentiated macrophages. Distal effects on ERK phosphorylation of the substrate P90RSK and release of IL1B followed the same pattern. The effect of MBZ on MEK/ERK phosphorylation was inhibited by RAF/MEK/ERK inhibitors in THP-1 models, CD3/IL2 stimulated PBMCs and a MAPK reporter HEK-293 cell line. MBZ was also shown to increase ERK activity in CD4+ T-cells from lupus patients with known defective ERK signalling. Given these mechanistic features MBZ is suggested suitable for treatment of diseases characterized by defective ERK signalling, notably difficult to treat autoimmune diseases. Mebendazole (MBZ) is an anti-parasitic drug that has gained considerable interest as a potential anticancer agent. MBZ is generally perceived as a tubulin polymerase inhibitor 1,2 but several other mechanisms have been suggested to explain the anticancer activity observed in vitro and in vivo. Mechanisms suggested include angiogenesis inhibition 3,4 , apoptosis induction 5,6 and inhibition of the Hedgehog signalling pathway 7. MBZ has also been shown to potently bind to several protein kinases involved in oncogenic signalling 8. Anticancer activity has also occasionally been observed in patients 9,10. Recently, we demonstrated that MBZ induces a pro-inflammatory tumour-suppressive M1 phenotype in THP-1 monocytes and macrophages which could potentially explain tumour cell killing 11. It was also noted that MBZ induced activation of ERK potentially contributes to the immune effects observed. ERK is part of a pathway which comprises proteins referred to as mitogen-activated protein kinases (MAPKs) 12. The MAPKs can be categorised into three major protein families: extracellular signal-regulated kinases (ERK), stress-activated protein kinases/c-Jun N-terminal kinase (SAPK/JNK) and the p38 proteins 12. Whereas SAPK/JNK is associated with stress response, apoptosis and inflammation, increased ERK is generally suggested to mediate cell survival, activation and differentiation 13. Proximal proteins involved in the ERK pathway include Ras, Raf and MEK 12. In the present study we investigated whether MBZ induced ERK activation is shared by other tubulin binding agents (TBAs) and if the ERK activation is observable also in other human cell typ...

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

Cited by 17 publications

References 25 publications

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs

Mebendazole is unique among tubulin-active drugs in activating the MEK–ERK pathway

In silicomolecular target prediction unveils mebendazole as a potent MAPK14 inhibitor

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