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Mebendazole is uniq...
Mebendazole is unique among tubulin-active drugs in activating the MEK-ERK pathway
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- Andersson, Claes (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Selvin, Tove (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Blom, Kristin (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Rubin, Jenny (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Berglund, Malin (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Jarvius, Malin (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Lenhammar, Lena (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Parrow, Vendela (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Loskog, Angelica S., 1973- (author)
- Uppsala universitet,Klinisk immunologi
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- Fryknäs, Mårten (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Nygren, Peter (author)
- Uppsala universitet,Experimentell och klinisk onkologi
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- Larsson, Rolf (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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(creator_code:org_t)
- 2020-08-04
- 2020
- English.
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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https://uu.diva-port... (primary) (Raw object)
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Abstract
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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.
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)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- art (subject category)
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- By the author/editor
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Andersson, Claes
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Selvin, Tove
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Blom, Kristin
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Rubin, Jenny
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Berglund, Malin
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Jarvius, Malin
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Lenhammar, Lena
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Parrow, Vendela
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Loskog, Angelica ...
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Fryknäs, Mårten
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Nygren, Peter
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Larsson, Rolf
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
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Scientific Repor ...
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Uppsala University