Journal of Natural Medicines ( IF 2.5 ) Pub Date : 2022-02-16 , DOI: 10.1007/s11418-022-01603-8 Jia Luo 1 , Juan Wang 1 , Jun Yang 1 , Wenjing Huang 1 , Junqiu Liu 2 , Wenfu Tan 1 , Hong Xin 1
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Medulloblastoma (MB), accounting for nearly 10% of all childhood brain tumors, are implicated with aberrant activation of the Hedgehog (Hh) signaling pathway. Saikosaponin B1 (SSB1) and Saikosaponin D (SSD), two bioactive constituents of Radix Bupleuri, are reported to have many biological activities including anticancer activities. In our work, we evaluated the inhibition of SSB1 and SSD on MB tumor growth in allograft mice and explored the underlying mechanisms. The associated biological activity was investigated in Shh Light II cells, an Hh-responsive fibroblast cell line, using the Dual-Glo® Luciferase Assay System. First, SSB1 (IC50, 241.8 nM) and SSD (IC50, 168.7 nM) inhibited GLI-luciferase activity in Shh Light II cells stimulated with ShhN CM, as well as Gli1 and Ptch1 mRNA expression. In addition, both compounds suppressed the Hh signaling activity provoked by smoothened agonist (SAG) or excessive Smoothened (SMO) expression. Meanwhile, SSB1 and SSD did not inhibit glioma-associated oncogene homolog (GLI) luciferase activity activated by abnormal expression of downstream molecules, suppressor of fuse (SUFU) knockdown or GLI2 overexpression. Consequently, SSB1 (30 mg/kg, ip) and SSD (10 mg/kg, ip) displayed excellent in vivo inhibitory activity in MB allografts, and the tumor growth inhibition ratios were approximately 50% and 70%, respectively. Our findings, thus, identify SSB1 and SSD significantly inhibit tumor growth in MB models by inhibiting the Hedgehog pathway through targeting SMO.
Graphical abstract
中文翻译：
Saikosaponin B1和Saikosaponin D通过抑制Hedgehog信号通路抑制髓母细胞瘤同种异体移植小鼠的肿瘤生长
髓母细胞瘤 (MB) 占所有儿童脑肿瘤的近 10%，与 Hedgehog (Hh) 信号通路的异常激活有关。据报道，柴胡的两种生物活性成分柴胡皂苷 B1 (SSB1) 和柴胡皂苷 D (SSD)具有多种生物活性，包括抗癌活性。在我们的工作中，我们评估了 SSB1 和 SSD 对同种异体移植小鼠 MB 肿瘤生长的抑制作用，并探索了潜在的机制。使用 Dual-Glo ®萤光素酶检测系统在 Shh Light II 细胞（一种 Hh 反应性成纤维细胞系）中研究了相关的生物活性。一、SSB1 (IC 50 , 241.8 nM) 和 SSD (IC 50, 168.7 nM) 在 ShhN CM 以及Gli1和Ptch1刺激的 Shh Light II 细胞中抑制 GLI 荧光素酶活性mRNA表达。此外，这两种化合物都抑制了由平滑激动剂 (SAG) 或过度平滑 (SMO) 表达引起的 Hh 信号活性。同时，SSB1 和 SSD 不抑制由下游分子异常表达、熔丝抑制剂 (SUFU) 敲低或 GLI2 过表达激活的胶质瘤相关癌基因同源物 (GLI) 荧光素酶活性。因此，SSB1 (30 mg/kg, ip) 和 SSD (10 mg/kg, ip) 在 MB 同种异体移植物中表现出优异的体内抑制活性，肿瘤生长抑制率分别约为 50% 和 70%。因此，我们的研究结果确定 SSB1 和 SSD 通过靶向 SMO 抑制 Hedgehog 途径显着抑制 MB 模型中的肿瘤生长。
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