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Article

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

1
Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
2
Mildred Scheel Cancer Career Center, University Cancer Center Hamburg, 20251 Hamburg, Germany
3
Department of Computer Science, University of Applied Sciences Bonn-Rhein-Sieg, 53757 Sankt Augustin, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to the study.
Academic Editor: Tsuyoshi Shimo
Int. J. Mol. Sci. 2021, 22(19), 10670; https://doi.org/10.3390/ijms221910670
Received: 22 August 2021 / Revised: 23 September 2021 / Accepted: 24 September 2021 / Published: 1 October 2021
(This article belongs to the Special Issue Hedgehog Signaling 3.0)
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. View Full-Text
Keywords: GLI; AML; MBZ; mebendazole; HSP90; HSP70 GLI; AML; MBZ; mebendazole; HSP90; HSP70
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MDPI and ACS Style

Freisleben, F.; Modemann, F.; Muschhammer, J.; Stamm, H.; Brauneck, F.; Krispien, A.; Bokemeyer, C.; Kirschner, K.N.; Wellbrock, J.; Fiedler, W. Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia. Int. J. Mol. Sci. 2021, 22, 10670. https://doi.org/10.3390/ijms221910670

AMA Style

Freisleben F, Modemann F, Muschhammer J, Stamm H, Brauneck F, Krispien A, Bokemeyer C, Kirschner KN, Wellbrock J, Fiedler W. Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia. International Journal of Molecular Sciences. 2021; 22(19):10670. https://doi.org/10.3390/ijms221910670

Chicago/Turabian Style

Freisleben, Fabian, Franziska Modemann, Jana Muschhammer, Hauke Stamm, Franziska Brauneck, Alexander Krispien, Carsten Bokemeyer, Karl N. Kirschner, Jasmin Wellbrock, and Walter Fiedler. 2021. "Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia" International Journal of Molecular Sciences 22, no. 19: 10670. https://doi.org/10.3390/ijms221910670

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