1,721,113 research outputs found
ANTIANGIOGENIC DRUGS AS CHEMOSENSITIZERS IN CANCER THERAPY
No full textAnti-angiogenic Drugs as Chemosensitizers in Cancer Therapy, Volume
18 focuses on the use of anti-angiogenic drugs as sensitizers of tumor cells to the inhibitory activity of antitumor agents. Conventional and novel anti- neoplastic agents (cytotoxic molecules, hormones/antihormones, immunotherapies) are taken into consideration, along with advances made in combination therapies. The book encompasses examples of studies on the use of antiangiogenic compounds—molecules that inhibit the growth of vessels inside a tumor—together with antineoplastic drugs in order to sensitize the resistant tumor to their cytotoxic effects, thus reducing adverse side reactions and resistance and improving the therapeutic response of cancer patients.
In addition, the book discusses clinical applications in various types of cancer, such as colorectal, lung, breast, renal, genitourinary, skin and circulating tumors.
It is a valuable resource for cancer researchers, clinicians and members of the biomedical field who wants to be up-to-date on the most recent and promising developments in the field
Polyphenol-based nutraceuticals for the control of angiogenesis: Analysis of the critical issues for human use
No full textAngiogenesis, the formation of new blood-vessel, is crucial in the pathogenesis of several diseases, and thus represents a druggable target for the prevention and treatment of different disorders. It is nowadays well kwon how diet can control cancer development and progression, and how the use of certain diet components can prevent cancer development. Several studies, also from our lab, now indicate that natural plant products including nutraceuticals modulate tumor angiogenesis. In this review, it is reported how phytochemicals, comprising hydroxytyrosol, resveratrol, genistein, curcumin, and the green tea component epigallocatechin-3-gallate among the others, negatively regulate angiogenesis. A single plant-derived compound may affect both endothelial and tumor cells, with the common denominator of anti-inflammatory and radical scavenger activities. Beside these positive features, documented in cellular and animal models, a series of critical issues should be considered from a pharmacological point of view as: what is the best source of bioactive compounds: food and beverages, extracted phytocomplexes, isolated nutraceuticals or synthetic analogues? How is the bioavailability of the compounds of interest in relation to the above source? Is there any biological activity by circulating metabolic derivatives? What is the best formulation, administration route and posology? How safe are in humans? How strong and reliable are the clinical trials designed for their use alone or in combination with conventional chemotherapy? After a dissertation of these critical points, the conclusion can be drawn that novel and effective strategies should be optimized to improve their bioavailability and efficacy, considering their exploitation as chemopreventive and/or curative approaches
General conclusions and future perspectives
No full textThe normalization of the tumor ecosystem, consisting in many different cell types and components, is an important new tool for cancer treatment. This chapter discusses the potential targets within the tumor microenvironment (TME) with pharmacological perspective on tumor vascularization and optimization of cancer treatments: hypoxic, acidic and oxidative environment responsible for angiogenic switch and chaotic neovascularization; switch of normal ECs (NECs) to tumor ECs (TECs) in term of cell behavior, metabolism and signaling; cancer associated fibroblasts (CAFs) mainly responsible for angiogenic factor release and processing of the extracellular matrix (ECM); macrophage recruitment in the TME to become tumor associated macrophages (TAMs) and differentiation toward M2 phenotype; normalization of the tumor vasculature; activation of the antitumoral activity by immune cells; miRNAs and epigenetic determinants. The combination of therapies targeting different stromal components, together with traditional antitumor agents, represents the key element to impair cancer progression. Ongoing studies in the field which focus on studying the TME with an integrative approach bear the potential to significantly control tumor angiogenesis and broaden the spectrum of current anticancer treatments
Therapeutic potential of nitric oxide donors in cancer: Focus on angiogenesis
No full textA new challenge to overcoming tumor resistance to conventional treatment is represented by the development of novel nitric oxide (NO) donors. It is now clear that while low doses of NO have proneoplastic properties, high doses exert antitumor/antiangiogenic activities through multiple mechanisms. This review focuses on the role of exogenous NO in cancer therapy and reports the state of the art regarding different NO-donating agents in cancer treatment, particularly in relation to angiogenesis inhibition
Molecular regulation of tumor angiogenesis by nitric oxide
No full textAs tumors grow, their original vasculature can be insufficient to supply the growing tissue mass, and consequently local hypoxia develops. Thus neovascularisation is a key feature determining growth and metastasis of malignant tumors. This is, at least in part, mediated by humoral factors known to stimulate angiogenesis, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). Among the multiple angiogenic modulators released by tumor and stromal cells, a key role is played by nitric oxide (NO). Beside its capacity to regulate permeability and blood flow, NO has been reported to exert angiogenic properties in various tumor models. The focus of this review will be the proangiogenic role of NO in the tumor microenvironment and its multiple mechanism of action on vascular endothelium. Particular attention will be devoted to the role of NO in regulating metalloproteinase activity on cultured microvascular endothelium and in the in vivo rabbit cornea assay. Finally, the potential clinical outcomes and expectations related to this topic will be discusse
Pharmacological modulation of endothelial function during tissue remodeling in physiopathological conditions
Full text linkVascular endothelium plays a pivotal role in the maintenance of many biological functions, including angiogenesis, defined as the formation of new capillaries from pre-existing vasculature. The process is aimed at supplying nutrients and oxygenation to growing or healing tissues following injury and, in the context of wound healing, endothelial cells lining the inner surface of blood vessels, are continuously engaged in a crosstalk with other cell types, immunity cells or fibroblasts, to assure a correct progression in the process of regeneration. Disruption of endothelial functions, which can occur for several reasons, including systemic administration of certain dugs or hyperglycemia, leads to a variety of pathological cardiovascular consequences which are commonly featured by inflammation and a dysregulation in pro-angiogenic factors release. Despite many efforts have been made to address this issue, endothelial dysfunction continues to be one of the main causes of morbidity and mortality all over the world, for which new therapeutical approaches are needed to prevent the damage or revert cardiovascular disorders.
The first aim of this thesis was to investigate the pro-angiogenic effect of erucin, a natural isothiocyanate with “smart” H2S-releasing properties, particularly abundant in the edible cruciferous plant Eruca sativa. In this study we characterized the pro-angiogenic effect of erucin on endothelial cells by using different functional in vitro assays aimed at evaluating cell migration and ability to organize in a capillary network. A special focus was paid to the molecular mechanisms involved in endothelial cell response to the compound by investigating the early activation of enzymes involved in angiogenesis, such as eNOS, ERK1/2, Akt. Secondly, we demonstrated erucin ability, alone or in combination with vascular endothelial growth factor (VEGF), to protect endothelial cells from high glucose-induced damage and recover impaired functional responses to physiological levels. In the second part of this topic we started to analyze the activity of the isothiocyanate in the context of wound healing by assessing in vitro its pro-migratory, pro- survival effect on dermal fibroblasts (NHDF) and keratinocytes (HaCaT). Lastly, a preliminary study using indirect co-cultures on NHDF and HUVEC, was carried out in order to investigate erucin ability to promote and sustain endothelial-stromal crosstalk, a fundamental step in wound healing.
The second part of my thesis addressed the role of activated fibroblasts in the context of impaired wound healing characterized by eccessive inflammation, which underlies several pathologic conditions ranging from healing delay to fibrosis. The aim was to characterize the cellular and molecular events associated with the anti-inflammatory activity of photobiomodulation therapy on human dermal fibroblasts exposed to a mix of inflammatory cytokines followed by laser treatment. Results demonstrated laser ability to revert fibroblast inflammatory phenotype by reducing to basal levels pro-angiogenic factors, as VEGF, and inducible inflammatory key enzymatic pathways, as iNOS and COX-2/mPGES-1/PGE2, by retaining NF-kB transcription factor in a cytoplasmic localization. These molecular changes are accompanied by a shift in cell morphology attributed to a re-distribution of fundamental cytoskeletal proteins (Tubulin, F- actin, and α-SMA) to basal localization following laser treatments.
In the third and final topic of this dissertation we discussed the importance of assuring endothelial safety during drug development. The cardiovascular system has proven to be particularly sensitive to a large variety of drugs, especially chemotherapeutic agents, which can promote or accelerate the onset of relevant cardiovascular diseases by impairing vascular integrity and tone. Recently, carbonic anhydrase IX (CA-IX), emerged as a promising new anticancer target for the treatment of solid hypoxic tumors and many efforts have been made to develop selective inhibitors for biomedical applications. In the last project presented, the safety profile of two CA-IX inhibitors, SLC-0111 and AA-06-05 on human endothelial cells was assessed
Nitric oxide and angiogenesis
No full textThe steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell--cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery
Chapter 1. Introducion, How tumor-endothelial cell communication within the tumor microenvironment affects angiogenesis
No full textAAngiogenesis, the formation of new blood vessels from preexisting ones, occurs when the high proliferation rate of cancer cells creates hypoxic zones in the tumor mass and influences the progression of tumors since it guarantees the oxygen and nutrient delivery and an efficient way for neoplastic cells to reach the bloodstream and metastasize. Tumor neovascularization is the result of an angiogenic switch, meaning the unbalance between pro- and antiangiogenic factors, in favor of the first ones. The majority of the angiogenesis modulators acting on endothelial cells derive from neoplastic cells, but a growing contribution is coming from other cells of the tumor microenvironment as cancer-associated fibroblasts, pericytes, macrophages and immune cells. On their site, tumor endothelial cells communicate with the other cellular components in favor of tumor progression. In this chapter the description of the major proangiogenic factors is provided together with the one on antiangiogenic molecules. The transcriptional and not transcriptional mechanisms responsible for their accumulation or downregulation are reported. The signaling pathways depending on the receptor (and coreceptor) activation are described. All these findings have allowed the development of antiangiogenic strategies, but at the same time may explain the mechanisms of antiangiogenic drug failure and resistance
Studying Nitric Oxide in Endothelial Cells
No full textThe field of biochemistry and pharmacology of nitric oxide (NO) has various clinical perspectives, such as cardiovascular and metabolic disorders; neurovascular and neurodegenerative diseases; muscular-skeletal disorders; ocular, respiratory, and a large series of inflammation-related pathologies; and, on top of these, infective and neoplastic diseases. In all these disorders, vascular endothelial cells (ECs) play a crucial role as both NO producers and NO responders. Depending on the pathology and pathophysiological mechanisms, different pharmacological approaches can be developed and used, either to stimulate NO synthases (NOS), improve NO availability, and activate downstream NO-related pathways or, on the opposite, to downregulate NOS, scavenge NO, and inhibit NO-related signaling. Introducing endothelial cell cultures, genetic manipulation, and molecular studies allows us to thoroughly investigate the role of NO and its signaling in EC functional responses and angiogenesis. The present chapter presents the cell types and the cellular assays used to study the functional aspects of NO-related strategies in vascular endothelium. By using selective biochemical inhibitors of signaling pathways, the involvement of intracellular messengers can be assessed and verified in functional responses associated with EC proliferation, migration, and permeability
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