TY  - JOUR
U1  - Zeitschriftenartikel, wissenschaftlich - begutachtet (reviewed)
A1  - Freisleben, Fabian
A1  - Modemann, Franziska
A1  - Muschhammer, Jana
A1  - Stamm, Hauke
A1  - Brauneck, Franziska
A1  - Krispien, Alexander
A1  - Bokemeyer, Carsten
A1  - Kirschner, Karl N.
A1  - Wellbrock, Jasmin
A1  - Fiedler, Walter
T1  - Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - GLI
KW  - AML
KW  - MBZ
KW  - mebendazole
KW  - HSP90
KW  - HSP70
UN  - https://nbn-resolving.org/urn:nbn:de:hbz:1044-opus-59494
SN  - 1422-0067
SS  - 1422-0067
U6  - https://doi.org/10.3390/ijms221910670
DO  - https://doi.org/10.3390/ijms221910670
PM  - 34639011
VL  - 22
IS  - 19
SP  - 19
S1  - 19
PB  - MDPI
CY  - Basel
ER  -