结直肠癌(CRC)是全球最常见的胃肠道癌症之一,可导致死亡。Hedgehog(HH)信号通路调节CRC的起始和进展。近年来,抑制HH途径已成为一种潜在的治疗策略。CynanbungigeninC(CBC)是一种新型的C21类固醇,先前已报道用于治疗髓母细胞瘤。然而,其水溶性差限制了其进一步研究。在这项研究中,通过对CBC的结构修饰,合成了6种新的CBC衍生物,其中四种表现出比CBC更好的水溶性。此外,评估了它们对CRC的抗增殖活性。发现CBC-1对三种类型的CRC细胞系表现出最好的抑制作用,这种效果优于CBC。机械上,根据qRT-PCR和Western印迹分析,CBC-1通过调节HH途径的mRNA和蛋白质来抑制CRC细胞的增殖。此外,细胞热移位分析结果表明,CBC-1通过靶向胶质瘤相关癌基因(GLI1)调节这一信号通路。此外,通过用GLI1siRNA转染或用CBC-1下调GLI1来诱导细胞凋亡。最后,体内结果表明,CBC-1显着减少CRC中的肿瘤大小并下调GLI1。因此,这项研究表明,CBC-1,一种来自天然产物的新的GLI1抑制剂,可能被开发为CRC治疗的潜在抗肿瘤候选药物。
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers that results in death in worldwide. The Hedgehog (HH) signalling pathway regulates the initiation and progression of CRC. Inhibiting the HH pathway has been presented as a potential treatment strategy in recent years. Cynanbungeigenin C (CBC) is a new type of C21 steroid that has been previously reported for the treatment of medulloblastoma. However, its further investigation was limited by its poor water solubility. In this study, six new CBC derivatives were synthesized through the structural modification of CBC, and four of them showed better water solubility than CBC. Moreover, their antiproliferative activities on CRC were evaluated. It was found that CBC-1 presented the best inhibitory effect on three types of CRC cell lines, and this effect was superior to that of CBC. Mechanistically, CBC-1 inhibited the proliferation of CRC cells through regulation of mRNA and proteins of the HH pathway according to qRT-PCR and Western blotting analysis. Furthermore, Cellular Thermal Shift Assay results indicated that CBC-1 regulated this signalling pathway by targeting glioma‑associated oncogene (GLI 1).In addition, cell apoptosis was induced increasingly by transfection with GLI 1 siRNA or treatment with CBC-1 to downregulate GLI 1. Last, the in vivo results demonstrated that CBC-1 significantly reduced tumour size and downregulated GLI 1 in CRC. Therefore, this study suggests that CBC-1, a new GLI 1 inhibitor derived from natural products, may be developed as a potential antitumour candidate for CRC treatment.