Mebendazole-induced M1 polarisation of THP-1 macrophages may involve DYRK1B inhibition

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

doi:10.1186/s13104-019-4273-5

Cited by 15 publications

(14 citation statements)

References 31 publications

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“…Several preclinical studies proved the efficacy of MBZ as an inhibitor of multiple processes accountable for tumor resistance and progression at nano- and micro-molar clinically reachable concentrations: unregulated angiogenesis [29,35,36,37], pro-survival pathways (such as SHH [39], XIAP [41], MAPK/ERK [43], and c-MYB [45]), protein kinases activation and expression (including VEGFR2 [35], BRAF [43,62], MEK [43], BCR–ABL [64]), matrix metalloproteinase 2 [32] and multi-drug resistance protein transporters P-gp and MRP1 [47]. In vitro, MBZ was also able to stimulate antitumoral immune response by polarization of macrophages towards M1 tumor-suppressive phenotype [66,67,68]. Mebendazole demonstrated synergy with different chemotherapeutic agents, allowing to overcome chemoresistance to cisplatin [56], TMZ [53], and anti-HER2 conjugates with anthracycline or gemcitabine [52].…”

Section: Discussionmentioning

confidence: 99%

“…Likewise, repurposing of “dirty” drugs such as MBZ, acting over a wide range of pro-tumoral mechanisms, could help to overcome precision therapy limits and synergize with approved agents. Mebendazole also shares some effects with new generation anticancer agents, as it is able to inhibit several kinases [43,62,64] and stimulate antitumoral immune response [66,67,68]. Mebendazole’s low cost is a double-edged sword, as the lack of expected profit might discourage funding from pharmaceutical companies seeking a return on investments [77].…”

Section: Discussionmentioning

confidence: 99%

“…Finally, the role of protein kinase DYRK1B (dual specificity tyrosine-phosphorylation-regulated kinase 1B) as a mediator of the immune-modulating activity of MBZ was explored in a recent study by the same group [68]. Mebendazole revealed to be a potent inhibitor of DYRK1B (IC 50 360 nM, Kd 7 nM).…”

Section: Preclinical Evidence Of Anticancer Activitymentioning

confidence: 99%

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Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature

Guerini

Triggiani

Maddalo

et al. 2019

Cancers

113

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Anticancer treatment efficacy is limited by the development of refractory tumor cells characterized by increased expression and activity of mechanisms promoting survival, proliferation, and metastatic spread. The present review summarizes the current literature regarding the use of the anthelmintic mebendazole (MBZ) as a repurposed drug in oncology with a focus on cells resistant to approved therapies, including so called “cancer stem cells”. Mebendazole meets many of the characteristics desirable for a repurposed drug: good and proven toxicity profile, pharmacokinetics allowing to reach therapeutic concentrations at disease site, ease of administration and low price. Several in vitro studies suggest that MBZ inhibits a wide range of factors involved in tumor progression such as tubulin polymerization, angiogenesis, pro-survival pathways, matrix metalloproteinases, and multi-drug resistance protein transporters. Mebendazole not only exhibits direct cytotoxic activity, but also synergizes with ionizing radiations and different chemotherapeutic agents and stimulates antitumoral immune response. In vivo, MBZ treatment as a single agent or in combination with chemotherapy led to the reduction or complete arrest of tumor growth, marked decrease of metastatic spread, and improvement of survival. Further investigations are warranted to confirm the clinical anti-neoplastic activity of MBZ and its safety in combination with other drugs in a clinical setting.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature

Guerini

Triggiani

Maddalo

et al. 2019

Cancers

113

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“… 3 Mebendazole may also target kinases. Mebendazole has been reported as a kinase inhibitor of TRAF2- and NCK-interacting kinase (TNIK), 32 vascular endothelial growth factor receptor 2 (VEGFR2), 11 dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B), 33 and both BRAF wild type and BRAFV600E. 6 Although targeted kinase inhibition has not demonstrated success in clinical trials for glioblastoma, mebendazole simultaneously combines multiple molecular targets in a single brain penetrant and well tolerated oral drug.…”

Section: Discussionmentioning

confidence: 99%

Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: results of a phase 1 clinical trial

Gallia

Holdhoff

Brem

et al. 2020

Neuro-Oncology Advances

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Background Mebendazole is an anthelmintic drug introduced for human use in 1971 that extends survival in preclinical models of glioblastoma and other brain cancers. Methods A single center dose escalation and safety study of mebendazole in 24 patients with newly diagnosed high-grade gliomas (HGG) in combination with temozolomide was conducted. Patients received mebendazole in combination with adjuvant temozolomide after completing concurrent radiation plus temozolomide. Dose escalation levels were 25, 50, 100 and 200 mg/kg/day of oral mebendazole. A 15-patient expansion cohort was conducted at the maximum tolerated dose of 200 mg/kg/day. Trough plasma levels of mebendazole were measured at 4, 8 and 16 weeks. Results Twenty-four patients (18 glioblastoma, 6 anaplastic astrocytoma) were enrolled with median age of 49.9 years. Four patients (at 200 mg/kg) developed elevated grade 3 ALT and/or AST after one month, which reversed with lower dosing or discontinuation. Plasma levels of mebendazole were variable but generally increased with dose. Kaplan Meier analysis showed a 21-month median survival with 43% of patients alive at two years and 25% at 3 and 4 years. Median progression free survival (PFS) from the date of diagnosis for 17 patients taking more than one month of mebendazole was 13.1 months (95% Confidence Interval: 8.8 to 14.6 months) but for seven patients who received less than one month of mebendazole PFS was 9.2 months (95% CI: 5.8 -13.0 months). Conclusion Mebendazole at doses up to 200 mg/kg demonstrated long-term safety and acceptable toxicity. Further studies are needed to determine mebendazole’s efficacy in patients with HGG.

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“…MBZ is known to bind to the colchicine binding site of tubulin but this is also the case for other benzimidazoles 24 , thus providing no simple explanation for the MBZ induced selective ERK activation. However, MBZ has been demonstrated to inhibit DYRK1b at low nM concentrations which can lead to ERK activation 25 , 26 . Moreover, MBZ also potently inhibits BRAF 8 which in cells with wild type RAF leads to paradoxical ERK activation 27 , 28 .…”

Section: Discussionmentioning

confidence: 99%

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

Andersson

Selvin

Blom

et al. 2020

Sci Rep

Self Cite

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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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Mebendazole-induced M1 polarisation of THP-1 macrophages may involve DYRK1B inhibition

Cited by 15 publications

References 31 publications

Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature

Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature

Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: results of a phase 1 clinical trial

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

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