Vascular toxicity is a frequent adverse effect of current anticancer chemotherapies and often results from endothelial dysfunction. Vascular endothelial growth factor inhibitors (VEGFi), anthracyclines, plant alkaloids, alkylating agents, antimetabolites, and radiation therapy evoke vascular toxicity. These anticancer treatments not only affect tumor vascularization in a beneficial manner, they also damage ECs in the heart. Cardiac ECs have a vital role in cardiovascular functions including hemostasis, inflammatory and coagulation responses, vasculogenesis, and angiogenesis. EC damage can be resulted from capturing angiogenic factors, inhibiting EC proliferation, survival and signal transduction, or altering vascular tone. EC dysfunction accounts for the pathogenesis of myocardial infarction, atherothrombosis, microangiopathies, and hypertension. In this review, we provide a comprehensive overview of the effects of chemotherapeutic agents on vascular toxicity leading to hypertension, microvascular rarefaction thrombosis and atherosclerosis, and affecting drug delivery. We also describe the potential therapeutic approaches such as vascular endothelial growth factor (VEGF)-B and prokineticin receptor-1 agonists to maintain endothelial function during or following treatments with chemotherapeutic agents, without affecting anti-tumor effectiveness.
Small molecules are widely used for the modulation of the molecular basis of diseases. This makes them the perfect tool for discovering and developing new therapeutics. In this work, we have established a library of small molecules in house and characterized its molecular and druglike properties. We have shown that most small molecules have molecular weights less than 450. They have pharmaceutically relevant cLogP, cLogS, and druglikeness value distributions. In addition, Meinox’s small molecule library contained small molecules with polar surface areas that are less than 60 square angstroms, suggesting their potent ability to cross the blood-brain barrier. Meinox’s small molecule library was also tested in vitro for pathologically distinct forms of cancer, including pancreatic adenocarcinoma PANC1, breast carcinoma MCF7, and lymphoblastic carcinoma RS4-11 cell lines. Analysis of this library at a dose of 1 μM allowed the discovery of potent, specific or broadly active anticancer compounds against pathologically distinct cancers. This study shows that in vitro analysis of different cancers or other phenotypic assays with Meinox small molecule library may generate novel and potent bioassay-specific compounds.
Background
The epicardial-mesothelial cells (EMCs) are essential regulators of cardiac growth and repairment process. The epicardial-to-mesenchymal transition (EMT) of epicardial fate determination are controlled by both cell autonomous and cardiomyocyte-originated mechanisms. Here, by using an in vitro and in vivo model of epicardial EMT, we investigated the role of miRNAs as regulators of these process and their potential targets.
Methods
EMT was induced in mice embryonic tcf21+EMCs through an angiogenic cytokine, prokineticin treatments. Cre-dependent tracing of TCF21-tm-iCRE-EMCs was utilized to abrogate prokineticin receptor-1 (PKR1) in mice epicardium. Human tcf21+ cardiac fibroblast (mainly originated from epicardial origin also utilized to study for their repairment signaling.
Results
Upon EMC-specific abrogation of PKR1 in early stages of cardiac development the TCF21-tm-iCREPKR1−/− mice exhibited 13±4% embryonic lethality due to a disconnection of epicardial cells from compact layer, failed expansion of the sub-epicardial space, and disruption of heterotypic cell interaction between epicardium and myocardium. EMT-RT profiler and enrichment analysis revealed an impaired EMT in TCF21-tm-iCREPKR1−/− hearts. Ingenuity Pathway Analysis on the EMT molecular network (e.g., Snai1, Snai2, B-catenin, N-cadherin, vimentin), specific to cardiac development and defects revealed MiR-124 as a part of this network that was inversely associated and down-stream of PKR1 in cultured Tcf21+ cells. Furthermore, protein expression of SNAIL2 was significantly downregulated in TCF21-tm-iCREPKR1−/− hearts and cultured Tcf21+ cells upon treatment with mir124 mimic. The luciferase reporter assay showed that miR124 directly targeted the 3'-untranslated region of SNAIL2 in EMCs. In a counter experiment, PKR1 gene replacement or mir124 inhibitor was able to rescue the impaired EMT-genes, and an increase in apoptosis and impaired proliferation in epicardium of embryonic TCF21-tm-iCREPKR1−/− hearts. Importantly, miRNA mimic in cultured tcf21 cells maintained epithelial features in EMCs, and increased EMT-associated transcripts and traits, such as apoptosis. In contrast, MiR124 is involved in wound healing process in tcf21+human CFs and EMCs.
Conclusion
This study shows the importance of a crosstalk between PKR1 and miR-124 with respect to EMT regulation during cardiac development and repair. Controlling fibroblast-committed EMT and pathological fibrotic remodeling is of increasing interest within the field of regenerative tissue engineering and development of interventional strategies after cardiac injury.
Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Fondation de France
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