2. Academic Validation
  3. Broussoflavonol F exhibited anti-proliferative and anti-angiogenesis effects in colon cancer via modulation of the HER2-RAS-MEK-ERK pathway

Broussoflavonol F exhibited anti-proliferative and anti-angiogenesis effects in colon cancer via modulation of the HER2-RAS-MEK-ERK pathway

  • Phytomedicine. 2024 Dec:135:156243. doi: 10.1016/j.phymed.2024.156243.
Yiying Zhu 1,  Xiaoli Li 2,  Grace Gar-Lee Yue 3,  Julia Kin-Ming Lee 1,  Si Gao 1,  Mengru Wang 2,  Chun Kwok Wong 4,  Wei-Lie Xiao 5,  Clara Bik-San Lau 6
Affiliations

Affiliations

  • 1 Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
  • 2 Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, and School of Pharmacy, Yunnan University, Kunming 650091, China.
  • 3 Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
  • 4 Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Chemical Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China.
  • 5 Key Laboratory of Medicinal Chemistry for Natural Resource of Ministry of Education, Yunnan Characteristic Plant Extraction Laboratory, Yunnan Research & Development Center for Natural Products, School of Chemical Science and Technology, and School of Pharmacy, Yunnan University, Kunming 650091, China. Electronic address: [email protected].
  • 6 Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China; Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China; School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China. Electronic address: [email protected].
PMID: 39547096 DOI: 10.1016/j.phymed.2024.156243
Abstract

Background: A prenylated flavonoid, broussoflavonol F (BFF), was isolated from Macaranga genus with cytotoxicities against various Cancer cells, though its underlying mechanisms have not been fully elucidated.

Hypothesis: This study aimed to investigate the anti-tumor and anti-angiogenesis activities of BFF and its underlying mechanisms in colon Cancer.

Method: In the in vitro study, the cytotoxic effects of BFF in human colon Cancer HCT-116 and LoVo cells were examined using MTT assay, BrdU assay and colony formation assay. The anti-proliferative effects of BFF in these cells were assessed via cell Apoptosis and cell cycle analysis using flow cytometry. The anti-angiogenesis effects of BFF in human endothelial HEMC-1 cells were also detected using scratch wound healing assay and tube formation assay. While the in vivo effects of BFF in colon Cancer were further examined in zebrafish embryos and HCT116 tumor-bearing mice. The underlying mechanisms of BFF were predicted using network pharmacology analysis, and Western blotting was performed to validate both in vitro and in vivo results.

Results: BFF exhibited cytotoxicities on 5 colon Cancer cell lines, as well as anti-proliferative activities via inducing Apoptosis and cell cycle arrest at the G0/G1 phase in HCT116 and LoVo cells. BFF at 1.25-5 µM also suppressed cell proliferation in these two colon Cancer cell lines by downregulating HER2, Ras, p-BRAF, p-MEK and p-Erk protein expressions. In addition, BFF at 2.5-5 µM could significantly decrease the length of subintestinal vessels of zebrafish embryos through decreasing mRNA expressions of NRP1a, PDGFba, PDGFRb, KDR, FLT1 and VEGRaa. Besides, BFF exhibited anti-angiogenesis activity via inhibiting cell proliferation, motility and tube formation in HMEC-1 cells. Furthermore, intraperitoneal administration of BFF (10 mg/kg) suppressed tumor growth and decreased the expression of tumor proliferation marker Ki-67 and angiogenesis marker CD31 in the tumor tissues in HCT116 tumor-bearing mice. BFF treatment could also significantly decrease expressions of Ras, p-BRAF, p-MEK and p-Erk in the tumor section, which are consistent with the in vitro results.

Conclusions: This study revealed the anti-tumor and anti-angiogenesis effects of BFF in colon Cancer. This is the first report of the in vitro and in vivo anti-proliferative activity of BFF in colon Cancer through regulating the HER2-RAS-MEK-ERK pathway. These findings further support the research development of BFF as an anti-cancer agent in colon Cancer.

Keywords

Anti-angiogenesis; Anti-proliferative; Broussoflavonol F; Colon cancer; Macaranga indica.

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