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Gastrodin Attenuates Colitis and Prevents Tumorigenesis in Mice by Interrupting TLR4/MD2/NF-κB Signaling Transduction
Zhilun Yu1, Bei Yue1, Ruiyang Gao1
1The MOE Key Laboratory of Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines, and the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine (SHUTCM), Shanghai, 201203, China.
Introduction:
Chronic inflammation is one of the causative factors for tumorigenesis. Gastrodin is a main active ingredient isolated from Gastrodia elata Blume, a famous medicinal herb with a long edible history.
Aim:
This study aimed to explore the effects of gastrodin on colitis-associated carcinogenesis (CRC) in mice and to elucidate its potential molecular mechanisms.
Methods:
Balb/c mice were induced with azoxymethane (AOM) and dextran sulfate sodium (DSS) for 12 weeks. Gastrodin (50 mg/kg) was administered via oral gavage three times per week until the end of the experiment. Disease indexes, including body weight, bloody diarrhea, colon length, histopathological score, and tumor size, were measured. Tumor cell proliferation was evaluated by BrdU incorporation assay and tumor cell cytotoxicity was assessed by cell counting kit (CCK-8). The expression levels of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling molecules, NF-κB luciferase, and pro-inflammatory cytokines were determined by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), immunoblotting, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), or reporter gene assays. The binding affinity between gastrodin and myeloid differentiation protein-2 (MD2) was analyzed by molecular docking and cellular thermal shift assay (CETSA).
Results:
Gastrodin administration was demonstrated to mitigate various CRC-related symptoms in mice, including weight loss, diarrhea, and tissue abnormalities. Notably, gastrodin suppressed tumor cell growth during colitis- associated tumorigenesis, resulting in fewer and smaller adenomas in the colon. Unlike irinotecan, a broadspectrum antitumor drug, gastrodin did not exhibit apparent cytotoxicity in various colorectal adenocarcinoma cell lines. Additionally, gastrodin downregulated TLR4/NF-κB signaling molecules and pro-inflammatory mediators in mice and macrophages. Molecular docking and CETSA experiments suggested that gastrodin binds to the MD2 protein, potentially interfering with the recognition of lipopolysaccharide (LPS) by TLR4, leading to NF-κB pathway inhibition.
Conclusion:
This study provides evidence for the first time that gastrodin attenuated colitis and prevented colitisrelated carcinogenesis in mice, at least partially, by diminishing tumor-promoting cytokines through the interruption of TLR4/MD2/NF-κB signaling transduction.
Insights
Gastrodin, derived from a medicinal herb, effectively reduced colitis and prevented colon cancer in mice by inhibiting the TLR4/MD2/NF-κB pathway. This natural compound offers a promising therapeutic strategy without significant cytotoxicity.
Area of Science:
- Gastroenterology
- Oncology
- Pharmacology
Background:
- Chronic inflammation is a key driver of cancer development.
- Gastrodin, a compound from Gastrodia elata Blume, is recognized for its medicinal properties.
Purpose of the Study:
- To investigate gastrodin's efficacy against colitis-associated carcinogenesis (CRC) in a mouse model.
- To elucidate the molecular mechanisms underlying gastrodin's anti-cancer effects.
Main Methods:
- CRC was induced in mice using azoxymethane (AOM) and dextran sulfate sodium (DSS).
- Gastrodin was administered orally, and disease progression was monitored via clinical and histological assessments.
- Molecular analyses included gene expression (RT-qPCR), protein levels (immunoblotting, IHC), cytokine assays (ELISA), and reporter gene assays to evaluate the TLR4/NF-κB pathway and MD2 binding.
Main Results:
- Gastrodin significantly ameliorated CRC symptoms, reducing tumor incidence and size in mice.
- Gastrodin suppressed tumor cell proliferation without causing cytotoxicity in colorectal cancer cell lines.
- The compound downregulated the TLR4/NF-κB signaling pathway and pro-inflammatory cytokines, with evidence of direct binding to MD2.
Conclusions:
- Gastrodin demonstrates therapeutic potential in preventing colitis-associated carcinogenesis.
- The anti-cancer effects are mediated, in part, by inhibiting the TLR4/MD2/NF-κB signaling pathway and reducing tumor-promoting cytokines.
