2. Academic Validation
  3. Targeting FGFR1 by β,β-dimethylacrylalkannin suppresses the proliferation of colorectal cancer in cellular and xenograft models

Targeting FGFR1 by β,β-dimethylacrylalkannin suppresses the proliferation of colorectal cancer in cellular and xenograft models

  • Phytomedicine. 2024 Jul:129:155612. doi: 10.1016/j.phymed.2024.155612.
Ran Zhao 1,  Fanxiang Yin 2,  Mangaladoss Fredimoses 3,  Jianhua Zhao 4,  Xiaorong Fu 4,  Beibei Xu 4,  Mengrui Liang 4,  Hanyong Chen 5,  Kangdong Liu 6,  Mingjuan Lei 3,  Kyle Vaughn Laster 3,  Zhi Li 7,  Joydeb Kumar Kundu 8,  Zigang Dong 9,  Mee-Hyun Lee 10
Affiliations

Affiliations

  • 1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou 450000, China.
  • 2 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Translational Medical Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.
  • 3 China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China.
  • 4 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China.
  • 5 The Hormel Institute, University of Minnesota, Austin, MN55912, USA.
  • 6 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000, China.
  • 7 Department of General Surgery, the Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou 450000, China.
  • 8 Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton AB T6G 2R3, Canada.
  • 9 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; Tianjian Laboratory of Advanced Biomedical Sciences, Zhengzhou 450000, China. Electronic address: [email protected].
  • 10 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China; China-US (Henan) Hormel Cancer Institute, Zhengzhou 450000, China; The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou 450000, China; College of Korean Medicine, Dongshin University, Naju 58245, Republic of Korea. Electronic address: [email protected].
PMID: 38669968 DOI: 10.1016/j.phymed.2024.155612
Abstract

Background: Colorectal Cancer (CRC) continues to be a major global health challenge, ranking as a top cause of cancer-related mortality. Alarmingly, the five-year survival rate for CRC patients hovers around a mere 10-30 %. The disruption of Fibroblast Growth Factor receptor (FGFRs) signaling pathways is significantly implicated in the onset and advancement of CRC, presenting a promising target for therapeutic intervention in CRC management. Further investigation is essential to comprehensively elucidate FGFR1's function in CRC and to create potent therapies that specifically target FGFR1.

Purpose: This study aims to demonstrate the oncogenic role of FGFR1 in colorectal Cancer and to explore the potential of β,β-dimethylacrylalkannin (β,β-DMAA) as a therapeutic option to inhibit FGFR1.

Methods: In this research, we employed a comprehensive suite of techniques including tissue array, kinase profiling, computational docking, knockdown assay to predict and explore the inhibitor of FGFR1. Furthermore, we utilized kinase assay, pull-down, cell proliferation tests, and Patient derived xenograft (PDX) mouse models to further investigate a novel FGFR1 Inhibitor and its impact on the growth of CRC.

Results: In our research, we discovered that FGFR1 protein is markedly upregulated in colorectal Cancer tissues, suggesting a significant role in regulating cellular proliferation, particularly in patients with colorectal Cancer. Furthermore, we conducted a computational docking, kinase profiling analysis, simulation and identified that β,β-DMAA could directly bind with FGFR1 within ATP binding pocket domain. Cell-based assays confirmed that β,β-DMAA effectively inhibited the proliferation of colon Cancer cells and also triggered cell cycle arrest, Apoptosis, and altered FGFR1-mediated signaling pathways. Moreover, β,β-DMAA effectively attenuated the development of PDX tumors in mice that were FGFR1-positive, with no notable toxicity observed. In summary, our study highlights the pivotal role of FGFR1 in colorectal Cancer, suggesting that inhibiting FGFR1 activity could be a promising strategy for therapeutic intervention. We present strong evidence that targeting FGFR1 with β,β-DMAA is a viable approach for the management of colorectal Cancer. Given its low toxicity and high efficacy, β,β-DMAA, as an FGFR1 Inhibitor, warrants further investigation in clinical settings for the treatment of FGFR1-positive tumors.

Keywords

Colorectal cancer; FGFR1; Kinase activity; PDX mouse model; Targeted therapy; β,β-dimethylacrylalkannin (β,β-DMAA).

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