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

内容摘要

Understanding of the possible vasoactive toxicities associated with platinum‑containing chemotherapeutic drugs for solid tumors remains limited. This study comprehensively identifies the vessel-threatening effects of cisplatin (CDDP), carboplatin (CBP), and oxaliplatin (OXA) and aims to compile an analytical model. A retrospective pharmacovigilance study was combined with network pharmacology analysis and in vitro experimental validation. 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. 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. 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. Are the risk of blood vessel damage by platinum-based chemotherapy drugs different? Evidence from real-world safety data and laboratory tests Many types of platinum-containing chemotherapy agents that can be applied in various kinds of cancer treatment. Although the anti-cancer effect is clear; The impact of them on Blood Vessels has been insufficiently studied. vascular Side Effects can lead to Problems such as fluctuations in blood pressure, thromboembolism or other clotting Disorders and dysfunction of vessel lumen. Combining large-scale real-world drug-safety Data with Laboratory experiments in combination for comparison of vascular Risks among Platinum Drugs and identification or exploration of potential Biological Mechanisms. Based on analysis of the world’s safety reports, all three agents had a high incidence rate of vascular complications soon after administration. oxaliplatin was most strongly associated with vascular events; carboplatin had the lowest risk. Laboratory experiment Results: Platinum compounds decrease the number of human endothelial cells and promote their death. Oxaliplatin inhibited the activity of a key antioxidant protection pathway; cisplatin up-regulated the expression of inflammatory adhesion molecules and caused similar endothelial dysfunction effects as oxaliplatin. Based on the above result, it has been found that increasing one’s age will trigger early vascular damage caused by platinum drugs; Moreover, different chemotherapy treatment methods have varying effectiveness outcomes.