1. Academic Validation
  2. CBC-1 as a Cynanbungeigenin C derivative inhibits the growth of colorectal cancer through targeting Hedgehog pathway component GLI 1

CBC-1 as a Cynanbungeigenin C derivative inhibits the growth of colorectal cancer through targeting Hedgehog pathway component GLI 1

  • Steroids. 2024 Apr 11:206:109421. doi: 10.1016/j.steroids.2024.109421.
Jinwen Chen 1 Wei Chen 1 Xiaoyu Li 2 Yiping Ye 3 Wenkang Huang 3 Lijuan Gao 4 Meng Zhang 5
Affiliations

Affiliations

  • 1 Department of Pharmacy, The First People's Hospital of Xiaoshan District, Hangzhou, Zhejiang 311200, China.
  • 2 Department of Pharmacy, The First People's Hospital of Xiaoshan District, Hangzhou, Zhejiang 311200, China. Electronic address: 775423305@qq.com.
  • 3 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 4 School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China. Electronic address: gaolijuan04141002@126.com.
  • 5 Department of Pharmacy, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China. Electronic address: 6522108@zju.edu.cn.
Abstract

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.

Keywords

CBC; Colorectal cancer; Derivatives; GLI inhibitors; Hedgehog signalling pathway.

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