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Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia

  • The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.

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Metadaten
Document Type:Article
Language:English
Author:Fabian Freisleben, Franziska Modemann, Jana Muschhammer, Hauke Stamm, Franziska Brauneck, Alexander Krispien, Carsten Bokemeyer, Karl N. Kirschner, Jasmin Wellbrock, Walter Fiedler
Parent Title (English):International Journal of Molecular Sciences
Volume:22
Issue:19
Article Number:10670
Pagenumber:19
ISSN:1422-0067
URN:urn:nbn:de:hbz:1044-opus-59494
DOI:https://doi.org/10.3390/ijms221910670
Publisher:MDPI
Place of publication:Basel
Publishing Institution:Hochschule Bonn-Rhein-Sieg
Date of first publication:2021/10/01
Keyword:AML; GLI; HSP70; HSP90; MBZ; Mebendazole
Departments, institutes and facilities:Fachbereich Informatik
Dewey Decimal Classification (DDC):5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Entry in this database:2021/10/12
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International