Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents

Morbidelli, Lucia; Donnini, Sandra; Ziche, Marina

doi:10.1186/s40959-016-0010-6

Cited by 25 publications

(23 citation statements)

References 117 publications

(155 reference statements)

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“…Taxanes are the cell-cycle targeting anticancer agents that inhibit mitosis by interfering with the mitotic spindle. It promotes formation of abnormal microtubules, which results in apoptosis of mitotically-arrested cells [38]. These changes affect cells in G2 and M cell cycle, which inhibits completion of division and leads to the accumulation of cells in G2 phase [39].…”

Section: The Influence Of Anti-cancer Agents On Endothelial Homeostasismentioning

confidence: 99%

“…Endothelial damage is also an adverse event of novel targeted therapies, especially inhibiting vascular endothelial growth factor (VEGF) [36,38,54,68]. This group of drugs includes monoclonal antibodies: bevacizumab -a humanised monoclonal antibody targeting VEGF, which is used in the treatment of breast, lung, colorectal, and renal cancers, as well as multiple kinase inhibitors: sunitinib, sorafenib -a multi-targeted inhibitor approved for treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumours (GIST) [36,54].…”

Section: The Influence Of Anti-cancer Agents On Endothelial Homeostasismentioning

confidence: 99%

“…The antiangiogenic multiple kinase inhibitors (sunitinib and sorafenib) target a range of different receptor tyrosine kinases and other intracellular kinases, and thus their effect on endothelial damage is much more complex [38]. Thijs et al [77] proved that in an animal model exposure to high concentrations of sunitinib diminishes FMD by reducing endothelial release of nitric oxide.…”

Section: The Influence Of Anti-cancer Agents On Endothelial Homeostasismentioning

confidence: 99%

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Anti-cancer agents and endothelium

et al. 2018

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Recent advances in oncology have improved the treatment outcomes and life expectancy of cancer patients; therefore, late effects of oncological treatment are of high clinical importance. Recent studies have shown that cardiovascular events are among the leading causes of premature morbidity in cancer survivors. Cardiotoxicity of some chemotherapeutic agents have been already confirmed; however, this issue seems to be more complex. Endothelium dysfunction is one of the first recognisable signs of atherosclerosis, which occurs long before the development of overt cardiovascular disease. Thus, it could be considered as an initial step, leading to increased risk of cardiovascular events. This process is not easy to recognise; however, there are some laboratory tests and imagining techniques that provide an insight into the progression of endothelial dysfunction. In this review we discuss the influence of oncological treatment on endothelium, according to the hypothesis that it increases cardiovascular morbidity and mortality in cancer survivors. Additionally, we present diagnostic and therapeutic measures that could reduce cardiovascular risk in cancer patients.

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Section: The Influence Of Anti-cancer Agents On Endothelial Homeostasismentioning

confidence: 99%

Section: The Influence Of Anti-cancer Agents On Endothelial Homeostasismentioning

confidence: 99%

Section: The Influence Of Anti-cancer Agents On Endothelial Homeostasismentioning

confidence: 99%

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Anti-cancer agents and endothelium

et al. 2018

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“…The vascular endothelium plays an important role in maintaining cardio-vascular homeostasis, and represents the first barrier for drugs and drug delivery systems to tissue diffusion and penetration [4]. The integrity of microvascular endothelial cells after iron oxide NPs intravenous administration has been only partially examined [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Monitoring Endothelial and Tissue Responses to Cobalt Ferrite Nanoparticles and Hybrid Hydrogels

et al. 2016

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Iron oxide nanoparticles (NPs) have been proposed for many biomedical applications as in vivo imaging and drug delivery in cancer treatment, but their toxicity is an ongoing concern. When NPs are intravenously administered, the endothelium represents the first barrier to tissue diffusion/penetration. However, there is little information about the biological effects of NPs on endothelial cells. In this work we showed that cobalt-ferrite (CoFe2O4) NPs affect endothelial cell integrity by increasing permeability, oxidative stress, inflammatory profile and by inducing cytoskeletal modifications. To overcome these problems, NPs have be loaded into biocompatible gels to form nanocomposite hybrid material (polysaccharide hydrogels containing magnetic NPs) that can be further conjugated with anticancer drugs to allow their release close to the target. The organic part of hybrid biomaterials is a carboxymethylcellulose (CMC) polymer, while the inorganic part consists of CoFe2O4 NPs coated with (3-aminopropyl)trimethoxysilane. The biological activity of these hybrid hydrogels was evaluated in vitro and in vivo. Our findings showed that hybrid hydrogels, instead of NPs alone, were not toxic on endothelial, stromal and epithelial cells, safe and biodegradable in vivo. In conclusion, biohydrogels with paramagnetic NPs as cross-linkers can be further exploited for antitumor drug loading and delivery systems.

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“…Thus, the presence of Crim1 could counter the pathophysiology of various diseases that are directly involved with endothelial abnormalities, such as atherothrombosis, hypertension and kidney failure, while maintaining homeostasis of the cardiovascular system and heart function on the whole , Rajendran, Rengarajan et al 2013, Morbidelli, Donnini et al 2016). …”

Section: Il1-b Sele Tnfsf10mentioning

confidence: 99%

Analysis of the Role of Crim1 in Heart Development

Iyer¹

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To overcome the societal and financial burden of cardiovascular disease, a thorough understanding of the molecular and cellular programmes governing cardiac and coronary vascular development is vital. Cre-mediated genetic tracing in various models has provided valuable insight into cell-lineage contribution and inductive cues required for cardiac morphogenesis. Using mouse models, we have identified the transmembrane protein Cysteine-Rich Transmembrane BMP Regulator-1 (Crim1) as an essential protein for numerous aspects of heart development. The presence of six Cysteine-Rich Repeats (CRRs) in Crim1 render it to be a versatile molecule -these have been shown to bind a wide range of growth factors when Crim1 is co-expressed in the same cell as the growth factor . The main objective of this thesis is to examine the role that Crim1 plays both temporally and spatially during heart development, and how it functions in tandem with other factors to ensure the progression of this critical process.Crim1 is strongly expressed in the proepicardium (PE), epicardium, coronary vascular smooth muscle cells and, to a weaker extent, in coronary endothelial cells .Interestingly, Crim1 mutant homozygotes die perinatally on a C57BL6 background . Loss of Crim1 function leads to a reduced ventricular size and hypoplastic ventricular compact myocardium, and abnormal epicardial morphology including blebbing and a loss of the regular, cobblestone appearance of the epicardium. Furthermore, epicardium-restricted deletion of Crim1 resulted in increased epicardial epithelial-to-mesenchymal transition (EMT) and invasion of the myocardium, while primary epicardial cells lacking Crim1 displayed an increased migration.Growth factors like TGFs are known to promote epicardial EMT; however, we observed a paradoxical reduction in epicardial TGF signalling in Crim1 mutant embryos. Interestingly, there appeared to be an accumulation of -catenin, a cell-adhesion molecule present at cadherindependent junctional complexes in epithelial cells, at epicardial cell-cell junctions, suggesting an interaction with Crim1 to promote stabilization of these junctions. There was also an increase in the level of phospho-ERK1/2 in the ventricular compact myocardium of mutants, though phospho-AKT levels remained unchanged. This indicates a cell-autonomous role for Crim1 in controlling epicardial migration, EMT and invasion, and a potential paracrine role in regulating myocardial development, likely through regulation of epicardium derived factors.Another notable defect observed in the absence of Crim1 is that the coronary vasculature also appears to be malformed. We found a reduction in coronary vascular endothelial cell endowment in We also sought to understand the role of Crim1 in growth factor modulation in endothelial cells in vivo. There was a decrease in phospho-SMAD1/5 activity in endothelial cells from ventricles of Crim1Δflox/Δflox homozygotes, suggesting a dysregulation of TGFβ/BMP signalling in these cells, confirming our in vitro data. However, t...

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Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents

Abstract: The vascular endothelium plays a

Cited by 25 publications

References 117 publications

Anti-cancer agents and endothelium

Anti-cancer agents and endothelium

Monitoring Endothelial and Tissue Responses to Cobalt Ferrite Nanoparticles and Hybrid Hydrogels

Analysis of the Role of Crim1 in Heart Development

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