Abstract
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.
Highlights
The Hedgehog (HH) signaling pathway is a highly conserved signaling cascade that plays a critical role during embryogenesis and is strongly involved in many basic cellular functions, including cell differentiation, proliferation and stem cell maintenance [1]
Since the 1987 discovery of GLI1 in human glioma cells [12], the role of the three members GLI1, GLI2 and GLI3 in a variety of cancers has become increasingly apparent [4], with GLI1 expression identified as a negative prognostic factor in numerous cancers [6,7]
We demonstrated that the treatment of GLI reporter AML cell lines with SMO-inhibitor cyclopamine did not lead to a reduction in GLI promoter activity [3]
Summary
The Hedgehog (HH) signaling pathway is a highly conserved signaling cascade that plays a critical role during embryogenesis and is strongly involved in many basic cellular functions, including cell differentiation, proliferation and stem cell maintenance [1]. Upon ligand binding Ptch releases SMO, a seven-transmembrane domain G-protein coupled receptor-like protein, which activates the GLI transcription factors representing the main effectors of the HH signaling pathway. In addition to this canonical HH pathway, numerous signaling cascades result in non-canonical activation of the GLI transcription factors, including FLT3/STAT5, RTK/RAF/MEK/ERK and PI3K/AKT/mTOR [2,3]. It is well established that aberrant activation of HH signaling is associated with a wide variety of neoplasms [4]. Expression of GLI1 is associated with a poor prognosis in a wide variety of cancers [6,7]. We showed that a high GLI1 and GLI2 expression represents a negative prognostic marker in AML, and that targeted inhibition of GLI1 and GLI2 mediates anti-leukemic effects in vitro and in vivo [7]
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