2. Academic Validation
  3. Amentoflavone inhibits colorectal tumor growth, stemness, and metastasis, prolonging survival through GLI-1/IL6/STAT3 axis targeting

Amentoflavone inhibits colorectal tumor growth, stemness, and metastasis, prolonging survival through GLI-1/IL6/STAT3 axis targeting

  • Biomed Pharmacother. 2025 Aug 11:191:118435. doi: 10.1016/j.biopha.2025.118435.
Yi-Jen Fang 1,  Cheng-Hsien Chen 2,  Hsiang-Ju Ku 3,  Dai-Cheng Dong 4,  Tsai-Lan Liao 5,  Fei-Ting Hsu 6
Affiliations

Affiliations

  • 1 Department of Post-Baccalaureate Medicine, College of Medicine, National Chung-Hsing University, Taichung 400, Taiwan; Digestive Disease Center, Changhua Show Chwan Memorial Hospital, Changhua 500, Taiwan.
  • 2 Surgical Intensive Care Unit, Department of Surgery, Changhua Show Chwan Memorial Hospital, Changhua 500, Taiwan.
  • 3 Institute of Biotechnology, National Tsing Hua University, Hsinchu 300, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 350, Taiwan.
  • 4 Department of Biological Science and Technology, China Medical University, Taichung 406, Taiwan; Department of Biomedical Engineering and Environmental Sciences, National Tsing-Hua University, Hsinchu 300, Taiwan.
  • 5 Department of Dentistry, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
  • 6 Department of Life Sciences, National Central University, Taoyuan 320, Taiwan. Electronic address: sakiro920@ncu.edu.tw.
PMID: 40795472 DOI: 10.1016/j.biopha.2025.118435
Abstract

Background: Colorectal Cancer (CRC) is a major malignancy of the colon and rectum. Despite recent clinical advances, continued research is essential to improve therapeutic outcomes. Amentoflavone, a naturally occurring biflavonoid with anti-inflammatory and anti-tumor properties, has shown potential, yet its precise mechanisms and therapeutic efficacy in CRC remain inadequately understood.

Materials and methods: CT26 and HCT116 cell lines were employed to evaluate the effects of amentoflavone on cell viability, metastasis, and stemness, both in vitro and in vivo.

Results: A high mutation rate of GLI-1 was observed in CRC patients and was correlated with increased expression of stemness-associated factors. Amentoflavone significantly inhibited GLI-1-mediated CRC cell proliferation, induced G1 phase arrest, and downregulated Cyclin D1/CDK4 expression. It also suppressed metastasis, as evidenced by reduced cell migration, invasion, angiogenesis, and epithelial-mesenchymal transition (EMT), largely through GLI-1 inactivation. Amentoflavone further diminished tumorsphere formation and stemness marker expression. Additionally, the IL-6/STAT3 signaling axis-positively correlated with GLI-1-was also inhibited by amentoflavone. In both xenograft and orthotopic mouse models, amentoflavone markedly reduced tumor growth and improved survival, as confirmed by CT imaging, 18F-FDG uptake, and Kaplan-Meier analysis. No signs of toxicity were observed, with normal organ histology, stable serum biochemistry (AST, ALT, γGT, CREA), and consistent body weight during treatment.

Conclusions: This preclinical study highlights amentoflavone as a promising and safe therapeutic candidate for CRC by targeting the GLI-1/IL-6/STAT3 signaling axis. These findings support further development of amentoflavone as a potential anti-CRC agent.

Keywords

Amentoflavone; G1-arrest; GLI-1; IL-6/STAT3; metastasis; stemness.

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