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

Abstract

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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Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways

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Quantitative Analysis of Cell Aggregation Dynamics Identifies HDAC Inhibitors as Potential Regulators of Cancer Cell Clustering

“…The CMap database contains over one million gene expression signatures upon treatment of a variety of cell types with many different perturbagens (from small-molecule compounds to gene overexpression and gene knockdown reagents). This resource has been successfully used in various studies in the field of cancer research to identify new candidates based on original signatures and to propose new drug repurposing opportunities (see for instance [ 22 , 23 , 24 , 25 ]). Changes in gene expression that arise from treatment with nearly 2500 perturbagens were compared with the expression signature deduced from our correlation analysis to find similarities.…”