ArticleAnnals of translational medicine2021
Metformin alleviates bevacizumab-induced vascular endothelial injury by up-regulating GDF15 and activating the PI3K/AKT/FOXO/PPARγ signaling pathway.
Article in Annals of translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 14 citations in OpenAlex.
- Luteolin alleviates inflammation by inhibiting the PI3K-Akt-FOXO3a pathway.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Piperine as a modulator of cancer hallmarks: mechanistic insights and therapeutic potential.Frontiers in oncology · 2026Review
- The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment.Journal of the American College of Cardiology · 2025Review
- Article
- Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review.International journal of molecular sciences · 2024Review
- Metformin alleviates bevacizumab-induced vascular endothelial injury in mice through growth differentiation factor 15 upregulation.Iranian journal of basic medical sciences · 2024Article
- BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression.Experimental & molecular medicine · 2023Article
- Clinical usefulness and acceleratory effect of macrophage inhibitory cytokine-1 on biliary tract cancer: an experimental biomarker analysis.Cancer cell international · 2022Article
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPrevious studies have reported that the combination of metformin and bevacizumab exhibit favorable efficacy in the treatment of cancer patients, and metformin possesses effects on relieving vascular injury in multiple diseases. Nonetheless, the effect of metformin in alleviating bevacizumab-induced vascular injury remains unknown. Therefore, the present study aimed to investigate the impact of metformin on apoptosis, vascular endothelial injury marker expressions, and inflammation in human umbilical vein endothelial cells (HUVECs), as well as its possible molecular mechanism.
methodsHUVECs were treated with bevacizumab, metformin or both, and subsequently treated with growth differentiation factor 15 (GDF15) overexpression plasmid, negative control (NC) plasmid, GDF15 small interfering ribonucleic acid (siRNA), NC siRNA, and the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, respectively. After treatment, apoptosis, levels of endothelial injury biomarkers and the potential downstream proteins were detected.
resultsBevacizumab increased the levels of apoptosis, vascular endothelial injury marker expressions and pro-inflammatory cytokine expressions in HUVECs, while metformin alleviated these effects in bevacizumab-treated HUVECs. Furthermore, GDF15 overexpression reduced the apoptosis, vascular endothelial injury marker expressions, pro-inflammatory cytokine expressions, and activated the PI3K/protein kinase B (AKT)/forkhead box O (FOXO)/peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway in bevacizumab-treated HUVECs. Subsequently, GDF15 siRNA reduced the effects of metformin on the bevacizumab-induced vascular endothelial injury (as described above) in HUEVCs. Lastly, the PI3K inhibitor exhibited similar effects to those of GDF15 siRNA in bevacizumab-treated HUVECs.
conclusionsMetformin protected against bevacizumab-induced vascular endothelial injury via activation of GDF15 and the PI3K/AKT/FOXO/PPARγ signaling pathway.
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