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Updated: Nov 6, 2025
Isolation, Enrichment, and Maintenance of Medulloblastoma Stem Cells
Published on: September 1, 2010
Identification of pseudolaric acid B as a novel Hedgehog pathway inhibitor in medulloblastoma
Su-Fen Wei1, Dan-Hua He2, Shi-Bing Zhang1
1Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
Abstract:
Aberrant activation of the Hedgehog (Hh) pathway is implicated in the pathogenesis and development of multiple cancers, especially Hh-driven medulloblastoma (MB). Smoothened (SMO) is a promising therapeutic target of the Hh pathway in clinical cancer treatment. However, SMO mutations frequently occur, which leads to drug resistance and tumor relapse. Novel inhibitors that target both the wild-type and mutant SMO are in high demand. In this study, we identified a novel Hh pathway inhibitor, pseudolaric acid B (PAB), which significantly inhibited the expression of Gli1 and its transcriptional target genes, such as cyclin D1 and N-myc, thus inhibiting the proliferation of DAOY and Ptch1+/- primary MB cells. Mechanistically, PAB can potentially bind to the extracellular entrance of the heptahelical transmembrane domain (TMD) of SMO, based on molecular docking and the BODIPY-cyclopamine binding assay. Further, PAB also efficiently blocked ciliogenesis, demonstrating the inhibitory effects of PAB on the Hh pathway at multiple levels. Thus, PAB may overcome drug-resistance induced by SMO mutations, which frequently occurs in clinical setting. PAB markedly suppressed tumor growth in the subcutaneous allografts of Ptch1+/- MB cells. Together, our results identified PAB as a potent Hh pathway inhibitor to treat Hh-dependent MB, especially cases resistant to SMO antagonists.
Insights
Pseudolaric acid B (PAB) is a novel inhibitor targeting the Hedgehog (Hh) pathway in medulloblastoma (MB). PAB effectively inhibits cancer cell proliferation and tumor growth, offering potential against drug-resistant cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Aberrant Hedgehog (Hh) pathway activation drives various cancers, including medulloblastoma (MB).
- Smoothened (SMO) is a key therapeutic target, but mutations cause drug resistance and relapse.
- Novel inhibitors targeting both wild-type and mutant SMO are crucial for effective cancer treatment.
Purpose of the Study:
- To identify and characterize a novel inhibitor of the Hh pathway.
- To evaluate the efficacy of pseudolaric acid B (PAB) against Hh-driven medulloblastoma.
- To investigate the mechanism of action of PAB in inhibiting SMO signaling.
Main Methods:
- In vitro assays using DAOY and Ptch1+/- primary MB cells.
- Analysis of Gli1 expression and downstream target genes (cyclin D1, N-myc).
- Molecular docking and BODIPY-cyclopamine binding assays to assess SMO interaction.
- Assessment of ciliogenesis inhibition.
- In vivo studies using subcutaneous allografts of Ptch1+/- MB cells.
Main Results:
- PAB significantly inhibited Gli1 expression and its target genes, suppressing MB cell proliferation.
- Molecular docking and binding assays suggest PAB binds to the SMO extracellular entrance.
- PAB effectively blocked ciliogenesis, indicating multi-level Hh pathway inhibition.
- PAB demonstrated significant tumor growth suppression in vivo.
- PAB showed potential to overcome SMO antagonist resistance.
Conclusions:
- Pseudolaric acid B (PAB) is a potent inhibitor of the Hh pathway.
- PAB effectively suppresses medulloblastoma growth and proliferation.
- PAB may overcome drug resistance associated with SMO mutations in clinical settings.
- PAB represents a promising therapeutic candidate for Hh-dependent MB, particularly resistant cases.
