NETWORK TOXICOLOGY FOR THE CARDIOVASCULAR TOXICITY ANALYSIS OF TYROSINE KINASE INHIBITORS

Öz

Objective: This study aims to explore potential molecular mechanisms and targets of cardiovascular toxicities caused by tyrosine kinase inhibitors. Therefore, toxicogenomic data mining was conducted focusing on sunitinib, sorafenib, pazopanib, axitinib, and their associations with cardiovascular diseases. Material and Method: Common genes between tyrosine kinase inhibitors and cardiovascular diseases were uncovered via comparative toxicogenomic databases. Additionally, protein-protein and gene-gene interactions were identified using STRING and GeneMANIA, respectively. Subsequently, hub proteins associated with tyrosine kinase inhibitor-induced cardiovascular diseases were determined through Metascape. Transcription factors and microRNAs related to this toxicity were identified using ChEA3 and MIENTURNET, respectively. Finally, gene ontology enrichment analysis and the most associated molecular pathways were identified using the DAVID database and Metascape, respectively. Result and Discussion: Toxicogenomic data mining revealed six genes common between tyrosine kinase inhibitors and cardiovascular diseases, with five of these genes (FLT1, FLT4, KDR, MAPK1, and MAPK3) identified as hub genes. Physical interaction was dominant among these hub genes (77.64%). Sunitinib, sorafenib, pazopanib, and axitinib generally downregulated the activities of these proteins. SOX17 and SOX18 were prominent among transcription factors, while hsa-miR-199a-3p was the most important microRNA associated with this toxicity. Moreover, the Ras signaling pathway was mostly associated with tyrosine kinase inhibitor-induced cardiovascular toxicities. These findings make a substantial contribution to understanding the processes underlying cardiovascular diseases induced by sunitinib, sorafenib, pazopanib, and axitinib. They also reveal novel potential therapeutic targets, including genes, proteins, transcription factors, microRNAs, and pathways.

Anahtar Kelimeler

• Cardiovascular diseases
• in silico data mining
• tyrosine kinase inhibitors

TİROZİN KİNAZ İNHİBİTÖRLERİNİN KARDİYOVASKÜLER TOKSİSİTE ANALİZİ İÇİN AĞ TOKSİKOLOJİSİ

Öz

Amaç: Bu çalışma, tirozin kinaz inhibitörlerinin neden olduğu kardiyovasküler toksisitelerin potansiyel moleküler mekanizmalarını ve hedeflerini araştırmayı amaçlamaktadır. Bu nedenle, sunitinib, sorafenib, pazopanib, axitinib ve bunların kardiyovasküler hastalıklarla ilişkilerine odaklanarak toksikogenomik veri madenciliği yapılmıştır. Gereç ve Yöntem: Tirozin kinaz inhibitörleri ile kardiyovasküler hastalıklar arasındaki ortak genler, karşılaştırmalı toksikogenomik veritabanları aracılığıyla belirlenmiştir. Ayrıca, protein-protein etkileşimleri ve gen-gen etkileşimleri sırasıyla STRING ve GeneMANIA kullanılarak belirlenmiştir. Daha sonra, tirozin kinaz inhibitörü ile ilişkilendirilmiş kardiyovasküler hastalıklara ait merkezi proteinler Metascape kullanılarak belirlenmiştir. Bu toksisite ile ilişkili transkripsiyon faktörleri ve mikroRNA'lar sırasıyla ChEA3 ve MIENTURNET kullanılarak belirlenmiştir. Son olarak, gen ontolojisi zenginleştirme analizi ve en çok ilişkilendirilen moleküler yollar sırasıyla DAVID veritabanı ve Metascape kullanılarak belirlenmiştir. Sonuç ve Tartışma: Toksikogenomik veri madenciliği, tirozin kinaz inhibitörleri ile kardiyovasküler hastalıklar arasında altı ortak geni ortaya çıkardı; bunlardan beşi (FLT1, FLT4, KDR, MAPK1 ve MAPK3) merkezi genler olarak belirlendi. Bu merkezi genler arasında fiziksel etkileşim baskın olarak gözlemlendi (%77.64). Sunitinib, sorafenib, pazopanib ve axitinib genel olarak bu protein aktivitelerini azaltmaktadır. Transkripsiyon faktörleri arasında SOX17 ve SOX18 öne çıkmaktadır, hsa-miR-199a-3p ise bu toksisite ile en önemli mikroRNA'dır. Ayrıca, Ras sinyal yolunun tirozin kinaz inhibitörleri ile ilişkilendirilen kardiyovasküler toksisitelerle çoğunlukla ilişkilendirildiği görülmüştür. Bu bulgular, sunitinib, sorafenib, pazopanib ve axitinib tarafından indüklenen kardiyovasküler hastalıkların altında yatan süreçleri anlamada önemli bir katkı yapmaktadır. Ayrıca, genler, proteinler, transkripsiyon faktörleri, mikroRNA'lar ve yollar da dahil olmak üzere yeni potansiyel terapötik hedefleri ortaya koymaktadır.

Anahtar Kelimeler

• İn siliko veri madenciliği
• kardiyovasküler hastalıklar
• tirozin kinaz inhibitörleri

Kaynakça

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