Comparison of pharmacovigilance and mechanism analysis of the vascular toxicity caused by platin-based chemotherapy: integration of FAERS analysis, network pharmacology, and endothelial validation

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Abstract
Background: Understanding of the possible vasoactive toxicities associated with platinum‑containing chemotherapeutic drugs for solid tumors remains limited. Objectives: This study comprehensively identifies the vessel-threatening effects of cisplatin (CDDP), carboplatin (CBP), and oxaliplatin (OXA) and aims to compile an analytical model. Design: A retrospective pharmacovigilance study was combined with network pharmacology analysis and in vitro experimental validation. Methods: Disproportionality analyses, including reporting odds ratio, proportional reporting ratio, empirical Bayesian geometric mean, and Bayesian confidence propagation neural network, were conducted to identify vascular adverse events (VAEs) related to the three drugs using data from the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2024. Network pharmacology was used to identify potential molecular targets and pathways. Human umbilical vein endothelial cells were treated with cisplatin, carboplatin, or oxaliplatin to evaluate cell viability (CCK-8 assay), apoptosis (flow cytometry), and gene expression by reverse transcription quantitative polymerase chain reaction (RT-qPCR) including Nrf2, ICAM1, VCAM1, NOS3, and HIF1A. Results: Among the 10,536 VAEs identified, all three drugs showed strong correlations with vascular events. Oxaliplatin had a correlation coefficient of 2.05 (95% confidence interval (CI): 1.99–2.11). Early failure characteristics (Weibull β ⩽ 1) were observed for all three drugs. The most frequently reported VAEs were hypotension, flushing, hypertension, and thrombosis. Network analysis highlighted the HIF-1, EGFR, and oxidative stress pathways. In vitro, oxaliplatin significantly reduced Nrf2 expression and cell viability, while cisplatin upregulated ICAM1 expression. Conclusion: Platinum compounds induce a short‑term vasoconstrictive effect, with oxaliplatin showing a relatively lower association. The results suggest activation of the oxidative stress pathway through Nrf2 inhibition and increased ICAM1 levels, alongside pathway‑specific alterations such as reduced HIF1A and NOS3 expression and decreased VCAM1 levels. Early cardiovascular monitoring and Nrf2‑targeted therapy warrant further investigation.
Funding Information
  • Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (JYY2023-14)
  • Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (JYY2023-15)

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