2. Academic Validation
  3. Identification of pseudolaric acid B as a novel Hedgehog pathway inhibitor in medulloblastoma

Identification of pseudolaric acid B as a novel Hedgehog pathway inhibitor in medulloblastoma

  • Biochem Pharmacol. 2021 Aug;190:114593. doi: 10.1016/j.bcp.2021.114593.
Su-Fen Wei 1,  Dan-Hua He 2,  Shi-Bing Zhang 1,  Yongzhi Lu 3,  Xiaowei Ye 4,  Xiang-Zhen Fan 1,  Hong Wang 1,  Qi Wang 5,  Yong-Qiang Liu 6
Affiliations

Affiliations

  • 1 Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
  • 2 Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
  • 3 Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 4 The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
  • 5 Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China. Electronic address: wangqi@gzucm.edu.cn.
  • 6 Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China; Research Center of Chinese Herbal Resources Science and Engineering, School of Pharmaceutical Sciences; Key Laboratory of Chinese Medicinal Resource from Lingnan, Ministry of Education, Guangzhou University of Chinese Medicine, Guangzhou 510006, China. Electronic address: liuyq@gzucm.edu.cn.
PMID: 33964282 DOI: 10.1016/j.bcp.2021.114593
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.

Keywords

Cilium; Drug resistance; Hedgehog pathway; Medulloblastoma; Smoothened antagonist; pseudolaric acid B.

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