Network Pharmacological Analysis Of The Underlying Mechanism Of Anti-tumor Drugs Induced Cardiovascular Diseases

Nowadays,the phenomenon that a variety of anti-tumor drugs may cause cardiovascular diseases has been reported and is increasingly concerned.However,the underlying molecular mechanisms of cardiovascular diseases induced by antitumor drugs remain elusive.To address this issue,corresponding drugs and their target genes were analyzed with network pharmacology approach,mainly including the structure and physicochemical properties of the drugs,tissue-specific localization,biological functions,signaling pathways,interaction network analysis.The main results are summarized as follows:Based on the analysis of drug structure and physical and chemical properties,the results showed that organic heterocyclics and benzene rings at the superclass level,carboxylic acids and their derivatives and benzene and their substituted derivatives at the class level are facing a higher risk of cardiovascular diseases.With larger log S,PSA and HAC values,the cardiovascular toxicity of the drug will be higher.In addition,through structural warning analysis of drug molecules,10 structural features related to cardiovascular toxicity(such as anthracycline,etc.)were revealed.These structural features will help to assess the cardiovascular toxicity risk of specific drugs.In addition,through functional analysis of the target genes of these drugs,it was found that the molecular functions associated with the target are mainly manifested in protein tyrosine kinase activity;biological processes mainly involve protein phosphorylation,regulation of ERK1 and ERK2 cascades,and other processes;cells components are mainly enriched in complex receptors,cell membranes and focal adhesions.Then,the signal pathways where the target genes located were enriched in Ras signaling pathway,MAPK signaling pathway,Rap1 signaling pathway and PI3-Akt signaling pathway.It indicates that these target genes are likely to cause cardiovascular disease toxicity through these signaling pathways.Furthermore,the results of our cross-talking analysis on these signaling pathways showed that these four pathways are modularized.This implied that not only Ras signaling pathways and Rap1 signaling pathways are also involved in cardiovascular toxicity,but also there is a synergistic correlation between them.And this module is likely to be connected to the major cancer-related pathways through the Regulation of actin cytoskeleton signaling pathway.Besides,the interaction network of target genes was analyzed from the network level.The hub genes mainly include EGFR(Epidermal growth factor receptor),ABL1(ABL proto-oncogene 1),AR(Androgen receptor),TUBB(Tubulin beta class I),TUBB1(Tubulin beta 1 class VI),RAF1(Raf-1 proto-oncogene),BCL2(BCL2 apoptosis regulator),TOP2A(DNA topoisomerase II alpha),PDGFRB(Platelet derived growth factor receptor beta),MAPT(Microtubule associated protein tau),indicating that these genes are likely to be the key to the regulation of cardiovascular toxicity gene.The enrichment analysis of GO-BP in function module 1 demonstrated that the related genes are mainly enriched in the regulation process of calcium ion release channels;the enrichment of signal pathways showed that they are mainly involved in shear stress and atherosclerosis,cytomegalovirus infection and C-type lectin receptor signaling pathway,etc.The GO-BP enrichment analysis of function module 2 indicated that the related genes were mainly enriched in the regulatory processes of peptidyl tyrosine and cell proliferation;the enrichment of signaling pathways showed that they were mainly involved in Ras,Rap1 and Erb B signaling pathways.This is also consistent with the our previous study,further indicating that the anti-tumor drugs studied are likely to cause cardiovascular disease toxicity through these signaling pathways.In summary,this research systematically explored the potential mechanism of cardiovascular disease induced by anti-tumor drugs,and revealed the key genes and possible signaling pathways.Although the method of network pharmacology still has limitations(no further experimental verification),it explains the process of disease development from the principles of systems biology,network biology,etc.,and uses a holistic view of network balance to unearth "multi-gene,multi-target" related to complex diseases.It has laid the foundation for deeper research on related molecular mechanisms.