Abstract
Background and Objective: Gastrointestinal cancer (GIC) stands as a leading cause of cancer-related mortality worldwide. Currently combination chemotherapy, particularly metal-based drugs, often induces side effects, limiting their clinical efficacy. Cardiotoxicity, a common complication associated with various therapeutic agents, manifests through vascular endothelial dysfunction, a hallmark of ischemic coronary disease. Our aim is to design novel metal-based drugs with enhanced efficacy, specificity, and mitigated off-target cytotoxicity. We identified the isomers trans and cis-[PtI2(isopropylamine)2] (I5 and I6, respectively), as promising candidates against GIC, both in vitro and in vivo 1. RNA seq was performed in 6 different GIC cells. The Gene Set Enrichment Analysis (GSEA) revealed a significant enrichment of inflammation-related genes and downregulation of angiogenesis-associated pathways in treated cells. Our objective now is to develop preclinical studies of the cardiovascular toxicity of I5 and I6. Methods: Cardiovascular effects of these drugs were studies using a in cellulo model system (AC16, HUVEC cell lines). Biological and biochemistry approaches and techniques were used to assess senescence, mitochondrial respiration, viability by MTS and wound healing assays. Results: Our findings indicate that both I5 and I6 decrease cellular viability, induce senescence (as evidenced by β-galactosidase activity), and generate reactive oxygen species compared to commonly used cisplatin. Additionally, I5 impact oxidative phosphorylation (OXPHOS) and glycolysis metabolism. Furthermore, a wound healing assay suggests that the migration of cells is modulated in response to treatment with these compounds. Conclusions: Accurate preclinical assessment of the effects of novel drugs on the vascular endothelium is imperative to address treatment-induced endothelial dysfunction before envisioning clinical trials. Understanding the impact of anti-cancer agents on the vascular endothelium will not only inform therapeutic strategies to prevent or reverse treatment-induced cardiotoxicity but may also serve as a vital tool for predicting, monitoring, and preventing adverse cardiovascular outcomes in patients undergoing cancer treatment. 1 Commun Biol 7, 353, doi:10.1038/s42003-024-06052-5 (2024).
Published Version
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