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  • Andersson, ClaesUppsala universitet,Cancerfarmakologi och beräkningsmedicin (author)

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

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • 2020-08-04
  • Springer Science and Business Media LLC,2020
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-417229
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-417229URI
  • https://doi.org/10.1038/s41598-020-68986-0DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

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  • Selvin, ToveUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)tovse668 (author)
  • Blom, KristinUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)kribl842 (author)
  • Rubin, JennyUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)jeeri172 (author)
  • Berglund, MalinUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)malbe920 (author)
  • Jarvius, MalinUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)maemi734 (author)
  • Lenhammar, LenaUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)lenalenh (author)
  • Parrow, VendelaUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)venpa974 (author)
  • Loskog, Angelica S.,1973-Uppsala universitet,Klinisk immunologi(Swepub:uu)angelosk (author)
  • Fryknäs, MårtenUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)mafry516 (author)
  • Nygren, PeterUppsala universitet,Experimentell och klinisk onkologi(Swepub:uu)peterng (author)
  • Larsson, RolfUppsala universitet,Cancerfarmakologi och beräkningsmedicin(Swepub:uu)rolflars (author)
  • Uppsala universitetCancerfarmakologi och beräkningsmedicin (creator_code:org_t)

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  • In:Scientific Reports: Springer Science and Business Media LLC10:12045-2322

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