RESUMEN
Raphanus sativus or radish is rich in bioactive compounds such as phenolic, antioxidant enzymes, carbohydrates, glucosinolates, terpenes, coumarins, alkaloids, flavonoids (anthocyanin), amino acids, carotenoids, organic acids, and isothiocyanates that have antioxidant and chemopreventive properties. The prominent compounds present in radish are glucosinolates, isothiocyanates, sulforaphane, flavonoids, phenethyl isothiocyanates, etc., that through various mechanisms play an important role in the prevention and treatment of various cancers such as, liver, prostate, colon, oral, lung, cervical, breast, blood, and gastric cancers. The major mechanisms involved are alterations in biotransformation enzymes, such as Phase I and Phase II enzymes, which could help the body detoxify or remove xenobiotics; apoptotic induction caused by secondary glucosinolate metabolites; anti-tumorigenesis through preventing angiogenesis, invasion, migration, and metastasis of cancer cells; using cell cycle arrest to limit the development of cancer cells; anti-proliferation; and antioxidant potential and modulation of epigenetic. These bioactive compounds also exhibit anti-tumor mechanisms that target various cancer cell lines. This review highlights the mechanistic role of various bioactive compounds present in Raphanus sativus for the treatment and prevention of various cancers and also explains their role in various cancer cell lines.
Asunto(s)
Inhibidores de la Angiogénesis , Antineoplásicos Fitogénicos , Apoptosis , Puntos de Control del Ciclo Celular , Neoplasias , Extractos Vegetales , Raphanus , Humanos , Raphanus/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Neoplasias/prevención & control , Neoplasias/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Animales , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéuticoRESUMEN
Introduction: Adrenomedullin (AM) is an autocrine/paracrine growth factor as well as a crucial regulator of angiogenesis and immune response. AM is overexpressed by most solid tumors, which makes it a good target for anti-tumor therapy. Methods: In this study, we designed and tested an mRNA vaccine directed against a fusion antigen composed by a small piece of keyhole limpet hemocyanin (KLH), as a hapten, and mouse AM. The in vitro-synthesized mRNA was encapsulated in lipid nanoparticles (LNPs) and injected in C57BL/6 mice. Empty LNPs were used as a negative control. After five immunizations, B16-F10 melanoma cells were injected through the tail vein to induce lung metastases. In addition, transgenic mice expressing green fluorescent protein in the blood vessels (SMAA-GFP) were also immunized with both LNP types to assess the potential side-effects of the vaccine on normal blood vessels. Results: Antibody titers against AM and the number of CD8+ T cells were significantly higher in AM-immunized mice than in negative controls. Furthermore, the number and size of the lung metastases, as well as the number of blood vessels, were significantly reduced in the AM-immunized group. In addition, no significant differences were observed in the number and distribution of existing blood vessels after immunization of the SMAA-GFP animals. Discussion: In summary, we have shown that an mRNA vaccine against the fusion KLH-AM peptide was able to break peripheral immunotolerance and induce a specific response against the angiogenic factor AM thus reducing tumor burden in the absence of disturbances to normal blood vessels.
Asunto(s)
Adrenomedulina , Vacunas contra el Cáncer , Neoplasias Pulmonares , Melanoma Experimental , Neovascularización Patológica , ARN Mensajero , Animales , Adrenomedulina/inmunología , Adrenomedulina/genética , Vacunas contra el Cáncer/inmunología , Ratones , Neovascularización Patológica/inmunología , Neovascularización Patológica/prevención & control , Melanoma Experimental/inmunología , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones Endogámicos C57BL , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/prevención & control , Carga Tumoral/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , ARN Mensajero/inmunología , ARN Mensajero/genética , Femenino , Nanopartículas , Ratones Transgénicos , Hemocianinas/inmunología , Hemocianinas/genética , AngiogénesisRESUMEN
BACKGROUND AND AIM: Sanguisorba officinalis L. and Sophora japonica L. (SOSJ) have been frequently used as medicinal pairs for treating ulcerative colitis (UC) due to their hemostatic properties. However, the mechanisms underlying their therapeutic effects remain unclear. This study aims to predict the targets of SOSJ for UC treatment using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS) and network pharmacology. METHODS: The efficacy of SOSJ was evaluated using a 3% dextrose sodium sulfate (DSS)-induced UC mice model. The general condition of the mice, histopathology, and expression of colonic inflammatory factors were assessed. Additionally, the effect of SOSJ on angiogenesis was evaluated by detecting the mRNA of colonic angiogenesis-related mediators, measuring microvessel density, and using transmission electron microscopy. RESULTS: SOSJ significantly attenuated inflammation and inhibited pathological angiogenesis in UC mice. It alleviated weight loss, colon shortening, and the presence of pus and blood in stools. SOSJ also reduced the mRNA expression levels of IL-6, IL-1ß, TNF-α, VEGF, VCAM1, Ang1, MMP1, MMP2, and MMP9. Furthermore, SOSJ decreased the protein expression of the PI3K-Akt pathway, an effect that could be reversed by 740Y-P, a specific PI3K activator. CONCLUSION: S. officinalis L. and S. japonica L. exert therapeutic effects on mice with ulcerative colitis, potentially through the modulation of angiogenesis and the PI3K-Akt signalling pathway.
Asunto(s)
Inhibidores de la Angiogénesis , Colitis Ulcerosa , Neovascularización Patológica , Fitoterapia , Extractos Vegetales , Sanguisorba , Sophora , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/metabolismo , Animales , Sophora/química , Sanguisorba/química , Modelos Animales de Enfermedad , Neovascularización Patológica/prevención & control , Neovascularización Patológica/tratamiento farmacológico , Masculino , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Colon/irrigación sanguínea , Colon/patología , Ratones , Ratones Endogámicos C57BL , Sulfato de Dextran , Transducción de Señal/efectos de los fármacos , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/aislamiento & purificación , Farmacología en Red , Sophora japonica , AngiogénesisRESUMEN
Aberrant angiogenesis is a hallmark of many pathologies. In cancer, tumor growth and metastasis strongly depend on angiogenesis triggered by neoplastic cells. Antiangiogenic therapies are approved to treat different kinds of cancer. However, the success of these treatments is so far limited as some patients do not respond at all and others develop resistances. Thus, a deeper understanding of the mechanisms driving tumor angiogenesis and the variations in tumor vessels is crucial. Optical coherence tomography angiography (OCTA) is a fast volumetric imaging technique that provides detailed insights into tumor vascularization and perfusion of vessels in a label-free and non-invasive manner. An ultra-high resolution OCTA and confocal fluorescence imaging pipeline are developed to analyze tumor vascularization and blood perfusion in vivo, using a zebrafish cancer model. OCTA imaging operating at 800 nm is optimized to show slow blood flow allowing to compare the functionality of blood vessels in healthy and tumor-bearing zebrafish. Furthermore, effects of small compounds on tumor vascularization can be investigated with our setup. The key outcomes include a qualitative assessment of vascularization and blood vessel perfusion, along with a quantitative analysis of vessel structure, to evaluate how effective the drugs were at different concentrations.
Asunto(s)
Inhibidores de la Angiogénesis , Neoplasias , Neovascularización Patológica , Animales , Pez Cebra , Neovascularización Patológica/diagnóstico por imagen , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Modelos Animales de Enfermedad , Inhibidores de la Angiogénesis/farmacología , Tomografía de Coherencia Óptica/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/irrigación sanguínea , AngiogénesisRESUMEN
The receptor tyrosine kinase EphB4 is involved in tumor angiogenesis, proliferation, and metastasis. Designed ankyrin repeat proteins (DARPins) binding to the EphB4 extracellular domain were identified from a combinatorial library using phage display. Surface plasmon resonance (SPR) allowed us to distinguish between DARPins that either compete with the EphB4 ligand ephrin-B2 for binding to a common site or target a different epitope. The identified DARPins all prevent ligand-induced EphB4 phosphorylation and impair tube formation by endothelial cells in vitro. The competitive DARPin AB1 was additionally shown to inhibit vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-induced angiogenesis in vivo. In summary, we have isolated DARPins that exert antiangiogenic effects by specifically binding to EphB4 and may potentially lead to new cancer therapeutics.
Asunto(s)
Inhibidores de la Angiogénesis , Efrina-B2 , Neovascularización Patológica , Receptor EphB4 , Transducción de Señal , Receptor EphB4/metabolismo , Receptor EphB4/antagonistas & inhibidores , Humanos , Efrina-B2/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Neovascularización Patológica/prevención & control , Neovascularización Patológica/metabolismo , Fosforilación/efectos de los fármacos , Ratones , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/química , Células Endoteliales de la Vena Umbilical Humana , Resonancia por Plasmón de Superficie , AngiogénesisRESUMEN
Endoplasmic reticulum stress (ERS) has recently been proposed as a core factor in the pathogenesis and aggravation of rosacea. The roles of ERS-related genes in rosacea are largely unknown and were investigated in this study. Rosacea microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed ERS-related genes in rosacea patients vs. controls were screened using the Limma package, and LASSO regression was used to screen for characteristic genes. The infiltrating fraction was evaluated using ssGSEA. Clinical rosacea samples, age-matched healthy volunteers, and LL37-induced mice models were used to investigate the expression of DNAJB2 and its function. In the GSE65914 dataset, 17 differentially expressed ERS-related genes were screened. Of these, 13 were identified as characteristic genes predicting rosacea risk. The adaptive immune response, TLR signaling pathway, and chemokine signaling pathway were activated with a high risk of rosacea. After expression validation using the GSE155141 dataset, DNAJB2 was identified as a key gene. DNAJB2 expression was significantly decreased in both datasets, clinical samples, and the LL37-induced mice model. DNAJB2 overexpression could alleviate rosacea skin injury and inhibit expression of inflammatory cytokines and chemokines as well as angiogenesis. The infiltration levels of the majority of immune cell types were elevated in rosacea samples, and DNAJB2 overexpression inhibited CD4 + T cell infiltration, as well as Th1 and Th17 polarizing genes. Moreover, DNAJB2 could inhibit ERS marker proteins and the activated TLR2/Myd88/NF-κB pathway. DNAJB2 may be a novel target for rosacea treatment.
Asunto(s)
Estrés del Retículo Endoplásmico , Proteínas del Choque Térmico HSP40 , Chaperonas Moleculares , Factor 88 de Diferenciación Mieloide , Neovascularización Patológica , Rosácea , Piel , Receptor Toll-Like 2 , Rosácea/metabolismo , Rosácea/patología , Rosácea/genética , Animales , Humanos , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/antagonistas & inhibidores , Estrés del Retículo Endoplásmico/fisiología , Ratones , FN-kappa B/metabolismo , FN-kappa B/antagonistas & inhibidores , Proteínas del Choque Térmico HSP40/metabolismo , Proteínas del Choque Térmico HSP40/genética , Transducción de Señal/fisiología , Factor 88 de Diferenciación Mieloide/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/prevención & control , Piel/patología , Piel/metabolismo , Piel/irrigación sanguínea , Inflamación , AngiogénesisRESUMEN
Xenohormesis proposes that phytochemicals produced to combat stressors in the host plant exert biochemical effects in animal cells lacking cognate receptors. Xenohormetic phytochemicals such as flavonoids and phytoalexins modulate a range of human cell signaling mechanisms but functional correlations with human pathophysiology are lacking. Here, potent inhibitory effects of grapefruit-derived Naringenin (Nar) and soybean-derived Glyceollins (Gly) in human microphysiological models of bulk tissue vasculogenesis and tumor angiogenesis are reported. Despite this interference of vascular morphogenesis, Nar and Gly are not cytotoxic to endothelial cells and do not prevent cell cycle entry. The anti-vasculogenic effects of Glyceollin are significantly more potent in sex-matched female (XX) models. Nar and Gly do not decrease viability or expression of proangiogenic genes in triple negative breast cancer (TNBC) cell spheroids, suggesting that inhibition of sprouting angiogenesis by Nar and Gly in a MPS model of the (TNBC) microenvironment are mediated via direct effects in endothelial cells. The study supports further research of Naringenin and Glyceollin as health-promoting agents with special attention to mechanisms of action in vascular endothelial cells and the role of biological sex, which can improve the understanding of dietary nutrition and the pharmacology of phytochemical preparations.
Asunto(s)
Flavanonas , Neovascularización Patológica , Fitoquímicos , Neoplasias de la Mama Triple Negativas , Humanos , Flavanonas/farmacología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/prevención & control , Fitoquímicos/farmacología , Femenino , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Pterocarpanos/farmacología , Inhibidores de la Angiogénesis/farmacología , Línea Celular Tumoral , Glycine max/química , Citrus paradisi/química , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , AngiogénesisRESUMEN
Cancer growth is dependent on angiogenesis, the formation of new blood vessels, which represents a hallmark of cancer. After this concept was established in the 1970s, inhibition of tumor development and metastases by blocking the neoangiogenic process has been an important approach to the treatment of tumors. However, antiangiogenic therapies are often administered when cancer has already progressed. The key to reducing the cancer burden is prevention. We noticed 20 years ago that a series of possible cancer chemopreventive agents showed antiangiogenic properties when tested in experimental models. This article reviews the relevant advances in the understanding of the rationale for targeting angiogenesis for cancer therapy, prevention, and interception and recently investigated substances with antiangiogenic activity that may be suitable for such strategies. Many compounds, either dietary derivatives or repurposed drugs, with antiangiogenic activity are possible tools for cancer angioprevention. Such molecules have a favorable safety profile and are likely to allow the prolonged duration necessary for an efficient preventive strategy. Recent evidence on mechanisms and possible use is described here for food derivatives, including flavonoids, retinoids, triterpenoids, omega fatty acids, and carotenoids from marine microorganisms. As examples, a number of compounds, including epigallocatechin, resveratrol, xanthohumol, hydroxytyrosol, curcumin, fenretinide, lycopene, fucoxanthin, and repurposed drugs, such as aspirin, ß blockers, renin-angiotensin-aldosterone inhibitors, carnitines, and biguanides, are reviewed.
Asunto(s)
Inhibidores de la Angiogénesis , Neoplasias , Neovascularización Patológica , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & control , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Neovascularización Patológica/patología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/farmacología , Animales , AngiogénesisRESUMEN
PURPOSE: Breast cancer metastasis relies on cellular invasion and angiogenesis facilitated by the downregulation of metastatic suppressor proteins like Cluster of Differentiation 82 (CD82). Currently, no medicines target multiple systems to prevent metastatic progression through CD82 upregulation. This study screened for plant extracts displaying effects on cell proliferation, invasion, and CD82 expression in breast cancer cells, and in vivo angiogenesis, and further correlated between the biological activities and effect on CD82 expression. METHODS: Seventeen ethanolic plant extracts were screened for their effect on cell proliferation (against MDA-MB-231 and MCF-7 breast cancer and Hek293 kidney cells), cell invasion and effect on CD82 expression in metastatic MDA-MB-231 cells. Selected extracts were further evaluated for in vivo anti-angiogenesis. RESULTS: Extracts displayed varying antiproliferative activity against the different cell lines, and those that showed selectivity indexes (SI) > 0.5 against MDA-MB-231 were selected for anti-invasion evaluation. Buddleja saligna Willd. (BS), Combretum apiculatum Sond. (CA), Foeniculum vulgare, Greyia radlkoferi, Gunnera perpensa and Persicaria senegalensis (Meisn.) Soják (PS) displayed 50% inhibitory concentration (IC50) values of 44.46 ± 3.46, 74.00 ± 4.48, 180.43 ± 4.51, 96.97 ± 2.29, 55.29 ± 9.88 and 243.60 ± 2.69 µg/mL, respectively against MDA-MB-231, and compared to Hek293 showed SI of 0.9, 0.7, 1.4, 1.1, 2.2 and 0.5. Significant invasion inhibition was observed at both 20 and 40 µg/mL for BS (94.10 ± 0.74 and 96.73 ± 0.95%) and CA (87.42 ± 6.54 and 98.24 ± 0.63%), whereas GR (14.91 ± 1.62 and 41 ± 1.78%) and PS (36.58 ± 0.54 and 51.51 ± 0.83%), only showed significant inhibition at 40 µg/mL, and FV (< 5% inhibition) and GP (10 ± 1.03 and 22 ± 1.31%) did not show significant inhibition at both concentrations. Due to the significant anti-invasive activity of BS, CA and PS at 40 µg/mL, these extracts were further evaluated for their potential to stimulate CD82. BS showed significant (p < 0.05) reduction in CD82 at 20 and 40 µg/mL (13.2 ± 2.2% and 20.3 ± 1.5% decrease, respectively), whereas both CA and PS at 20 µg/mL increased (p < 0.05) CD82 expression (16.4 ± 0.8% and 5.4 ± 0.6% increase, respectively), and at 40 µg/mL significantly reduced CD82 expression (23.4 ± 3.1% and 11.2 ± 2.9% decrease, respectively). Using the yolk sac membrane assay, BS (59.52 ± 4.12 and 56.72 ± 3.13% newly formed vessels) and CA (83.33 ± 3.17 and 74.00 ± 2.12%) at both 20 and 40 µg/egg showed significant (p < 0.001) angiogenesis inhibition, with BS showing statistical similar activity to the positive control, combretastatin A4 (10 nmol/egg), whereas PS only displayed significant (p < 0.001) angiogenesis stimulation at 40 µg/egg (120.81 ± 3.34% newly formed vessels). CONCLUSION: BS exhibits antiproliferative, anti-invasive, and anti-angiogenic activity despite inhibiting CD82, suggesting an alternative mode of action. CA at 20 µg/mL shows moderate anti-invasive and anti-angiogenic potential by stimulating CD82, while at 40 µg/mL it still displays these properties but inhibits CD82, suggesting an additional mode of action. PS, with the least antiproliferative activity, stimulates CD82 and inhibits angiogenesis at 20 µg/mL but inhibits CD82 and increases angiogenesis at 40 µg/mL, indicating CD82 targeting as a major mode of action. Future studies should explore breast cancer xenograft models to assess the extracts' impact on CD82 expression and angiogenesis in the tumor microenvironment, along with isolating bioactive compounds from the extracts.
Asunto(s)
Neoplasias de la Mama , Proliferación Celular , Proteína Kangai-1 , Invasividad Neoplásica , Neovascularización Patológica , Extractos Vegetales , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Femenino , Animales , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/patología , Neovascularización Patológica/prevención & control , Proteína Kangai-1/metabolismo , Plantas Medicinales/química , Células HEK293 , Línea Celular Tumoral , Etanol/química , Etanol/farmacología , Embrión de Pollo , Metástasis de la Neoplasia , Membrana Corioalantoides/efectos de los fármacos , AngiogénesisRESUMEN
Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, thereby inhibiting metastasis initiation. In this study, we report that the antitumor peptide JP1 regulated mitochondrial metabolic reprogramming through AMPK/FOXO3a/UQCRC2 signaling, which improved the tumor microenvironment hypoxia. The oxygen-rich tumor microenvironment inhibited the secretion of IL-8 by tumor cells, thereby promoting tumor vascular normalization. The normalized vasculature resulted in mature and regular blood vessels, which made the tumor microenvironment form a benign feedback loop consisting of vascular normalization, sufficient perfusion, and an oxygen-rich microenvironment, prevented tumor cells from entering the vasculature, and inhibited metastasis initiation. Moreover, the combined therapy of JP1 and paclitaxel maintained a certain vascular density in the tumor and promoted tumor vascular normalization, increasing the delivery of oxygen and drugs and enhancing the antitumor effect. Collectively, our work highlights the antitumor peptide JP1 as an inhibitor of metastasis initiation and its mechanism of action.
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Interleucina-8 , Neoplasias , Humanos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Neovascularización Patológica/patología , Neoplasias/tratamiento farmacológico , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Oxígeno , Microambiente TumoralRESUMEN
Berberine (BBR), a traditional Chinese phytomedicine extracted from various parts of Berberis plants, is an isoquinoline alkaloid used for centuries to treat diabetes, hypercholesterolemia, hypertension, and so forth. It has recently received immense attention worldwide to treat cancer due to its potent pro-apoptotic, antiproliferative, and anti-inflammatory properties. BBR efficiently induces tumor apoptosis, replicative quiescence and abrogates cell proliferation, epithelial-mesenchymal transition, tumor neovascularization, and metastasis by modulating diverse molecular and cell signaling pathways. Furthermore, BBR could also reverse drug resistance, make tumor cells sensitive to current cancer treatment and significantly minimize the harmful side effects of cytotoxic therapies. This review comprehensively analyzed the pharmacological effects of BBR against the development, growth, progression, metastasis, and therapy resistance in wide varieties of cancer. Also, it critically discusses the significant limitations behind the development of BBR into pharmaceuticals to treat cancer and the future research directions to overcome these limitations.
Asunto(s)
Antineoplásicos , Berberina , Resistencia a Antineoplásicos , Medicamentos Herbarios Chinos , Neoplasias , Berberina/farmacología , Berberina/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & control , Humanos , Resistencia a Antineoplásicos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Metástasis de la Neoplasia , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/prevención & controlRESUMEN
Platycodin D is a major constituent in the root of Platycodon grandiflorum and has diverse pharmacologic activities, including anti-inflammatory, anti-allergic, and antitumor activities. Vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) are potent angiogenic factors and contribute to tumor angiogenesis by directly and indirectly promoting angiogenic processes, including the proliferation, adhesion, migration, and tube formation of endothelial cells. Here, we found that platycodin D at noncytotoxic concentrations inhibited VEGF-induced proliferation, adhesion to the extracellular matrix proteins fibronectin and vitronectin, chemotactic motility, and tube formation of human umbilical vein endothelial cells (HUVECs). Platycodin D reduced the phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) and the secretion of IL-8 in VEGF-stimulated HUVECs. Moreover, platycodin D inhibited tube formation and the phosphorylation of ERK and p38 in IL-8-stimulated HUVECs. The in vitro anti-angiogenic activity of platycodin D was confirmed by in vivo experimental models. Platycodin D inhibited the formation of new blood vessels into mouse Matrigel plugs with VEGF or IL-8. In mice injected with MDA-MB-231 human breast cancer cells, orally administered platycodin D inhibited tumor growth, the number of CD34 [Formula: see text]vessels, and the expression of VEGF and IL-8. Taken together, platycodin D directly and indirectly prevents VEGF-induced and IL-8-induced angiogenesis by blocking the activation of mitogen-activated protein kinases (MAPKs). Platycodin D may be beneficial for the prevention or treatment of tumor angiogenesis and angiogenesis-related human diseases.
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Interleucina-8 , Factor A de Crecimiento Endotelial Vascular , Inhibidores de la Angiogénesis/farmacología , Animales , Movimiento Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Interleucina-8/metabolismo , Ratones , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Saponinas , Triterpenos , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular/metabolismo , Factores de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
The serine/arginine-rich protein kinase-1 (SRPK1) is an enzyme that has an essential role in regulating numerous aspects of mRNA splicing. SRPK1 has been reported to be overexpressed in multiple cancers, suggesting it as a promising therapeutic target in oncology. No previous studies reported the role of SRPK1 in cholangiocarcinoma (CCA) cells. This study aimed to examine the expression of SRPK1 and the effects of SRPK1 inhibition on the viability and angiogenesis activity of CCA cells using a selective SRPK1 inhibitor, SPHINX31. Here, we demonstrate that SPHINX31 (0.3-10 µM) had no inhibitory effects on CCA cells' viability and proliferation. However, SPHINX31 decreased the mRNA expression of pro-angiogenic VEGF-A165a isoform. In addition, SPHINX31 attenuated SRSF1 phosphorylation and nuclear localization, and increased the ratio of VEGF-A165b/total VEGF-A proteins. Moreover, when HUVECs were grown in conditioned medium from SPHINX31-treated CCA cells, migration slowed, and tube formation decreased. The present study demonstrates that targeting SRPK1 in CCA cells effectively attenuates angiogenesis by suppressing pro-angiogenic VEGF-A isoform splicing. These findings suggest a potential therapeutic treatment using SRPK1 inhibitors for the inhibition of angiogenesis in cholangiocarcinoma.
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Colangiocarcinoma , Proteínas Serina-Treonina Quinasas , Arginina , Humanos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/uso terapéutico , ARN Mensajero , Serina , Factores de Empalme Serina-Arginina/genética , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: The Breast Reconstruction Evaluation of Acellular Dermal Matrix as a Sling Trial is a single-center, blinded, prospective, randomized, controlled trial established to compare outcomes using two popular types of acellular dermal matrices, AlloDerm and DermaMatrix, in tissue expander breast reconstruction. This study used the acellular dermal matrix biopsy specimens from the trial to evaluate how adjuvant therapy influences inflammation, neovascularization, and capsule formation of the acellular dermal matrix. METHODS: Punch biopsy specimens were taken at the time of expander exchange and were analyzed by a blinded pathologist. The inflammatory response was quantified by the number of fibroblasts, giant cells, and lymphocytes. Neovascularization and capsule formation were similarly quantified by the number of new capillaries and capsule presence and thickness, respectively. RESULTS: Histology specimens were collected from 109 patients (170 breasts). In the absence of adjuvant therapy, there was no significant difference between AlloDerm and DermaMatrix in terms of inflammation, neovascularization, or capsule thickness. Both acellular dermal matrices showed a significant decrease in inflammation and neovascularization with adjuvant therapy. When chemotherapy and radiation therapy were used, the decrease in inflammation was greatest for the group reconstructed with DermaMatrix (p < 0.039). CONCLUSIONS: Adjuvant therapy influences the inflammatory response, neovascularization, and capsule formation in both acellular dermal matrices. Adjuvant therapy has a protective effect on the inflammatory response toward both acellular dermal matrices in breast reconstruction. In the setting of chemotherapy and radiation therapy, DermaMatrix produced the greatest reduction in inflammation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.
Asunto(s)
Dermis Acelular , Mama/patología , Quimioradioterapia Adyuvante , Inflamación/patología , Mamoplastia/métodos , Neovascularización Patológica/patología , Complicaciones Posoperatorias/patología , Antineoplásicos/farmacología , Biopsia , Mama/efectos de los fármacos , Mama/efectos de la radiación , Mama/cirugía , Femenino , Estudios de Seguimiento , Humanos , Inflamación/diagnóstico , Inflamación/etiología , Inflamación/prevención & control , Neovascularización Patológica/diagnóstico , Neovascularización Patológica/etiología , Neovascularización Patológica/prevención & control , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/prevención & control , Estudios Prospectivos , Método Simple Ciego , Expansión de Tejido/métodos , Resultado del TratamientoRESUMEN
Mahanimbine (MN) is a carbazole alkaloid present in the leaves of Murraya koenigii, which is an integral part of medicinal and culinary practices in Asia. In the present study, the anticancer, apoptotic and anti-invasive potential of MN has been delineated in vitro. Apoptosis cells determination was carried out utilizing the acridine orange/propidium iodide double fluorescence test. During treatment, caspase-3/7,-8, and-9 enzymes and mitochondrial membrane potentials (Δψm) were evaluated. Anti-invasive properties were tested utilizing a wound-healing scratch test. Protein and gene expression studies were used to measure Bax, Bcl2, MMP-2, and -9 levels. The results show that MN could induce apoptosis in MCF-7 cells at 14 µM concentration IC50. MN-induced mitochondria-mediated apoptosis, with loss in Δψm, regulation of Bcl2/Bax, and accumulation of ROS (p ≤ 0.05). Caspase-3/7 and -9 enzyme activity were detected in MCF-7 cells after 24 and 48 h of treatment with MN. The anti-invasive property of MN was shown by inhibition of wound healing at the dose-dependent level and significantly suppressed mRNA and protein expression on MMP-2 and -9 in MCF-7 cells treated with a sub-cytotoxic dose of MN. The overall results indicate MN is a potential therapeutic compound against breast cancer as an apoptosis inducer and anti-invasive agent.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Carbazoles/farmacología , Supervivencia Celular/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Murraya/química , Neovascularización Patológica/prevención & control , Hojas de la Planta/química , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Invasividad Neoplásica/prevención & control , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Quercetin (Que) exhibits excellent biological activity; however, its clinical development is hindered owing to the poor water solubility. In this study, Que. was loaded on polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG, Soluplus) micelles through a thin-film hydration process, and their tumor angiogenesis inhibition ability was investigated. The particle size of Soluplus-Que micelles was 55.3 ± 1.8 nm, and the micelles stayed stability within 9 months. Soluplus-Que micelles can enhance the cell uptake of Que. and transport the micelles to intracellular lysosomes and mitochondria. The MTT assay results revealed that Soluplus-Que micelles enhanced the cytotoxicity of Que. on HUVEC cells. Furthermore, Soluplus-Que micelles inhibited migration and invasion of HUVEC cells, as well as inhibited the neovascularization of chick embryo allantoic membrane (CAM). The in vivo study revealed that Soluplus-Que micelles significantly inhibit the growth of H22 solid tumors, with low toxic side effects. Soluplus-Que inhibited the expression of CD31 (a marker of angiogenesis) and the PI3K/Akt/VEGF pathway in tumor tissues, indicating its potential to hold back tumor growth via the inhibition of angiogenesis. Our findings indicated that as a delivery system, Soluplus micelles demonstrate potential for the delivery of poorly soluble drugs for tumor treatment.
Asunto(s)
Micelas , Neovascularización Patológica/prevención & control , Fosfatidilinositol 3-Quinasas/metabolismo , Polietilenglicoles/química , Polímeros/química , Polivinilos/química , Quercetina/farmacología , Inhibidores de la Angiogénesis , Animales , Movimiento Celular/efectos de los fármacos , Embrión de Pollo , Sistemas de Liberación de Medicamentos/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quercetina/química , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cancer is a multistep disease and its management is exceedingly expensive. Nowadays medicinal plants are gaining more attention in drug discovery and approximately 70% of anticancer drugs were developed from natural products or plants. A strong candidate from medicinal plant with anticancer potential should have four major properties: antioxidant, anti-inflammatory, anti-angiogenic, and cytotoxic activities. AIM OF THE STUDY: In order to assess Togolese traditional healer's claims about the anticancer potential of medicinal plants and obtain candidate plants for anticancer drug discovery, some species were selected from surveys and evaluated for their antioxidant, anti-inflammatory, anti-angiogenic and cytotoxic activities. METHODS: Four species, Cochlospermum planchonii (CP), Piliostigma thonningii (PT), Paullinia pinnata (PP), and Securidaca longipedunculata (SL) were selected and analyzed to detect the phytochemical components. The mentioned bioactivities were evaluated using in vitro, ex vivo and in vivo assays. RESULTS: Relative to SL extract, CP and PT have shown significantly high polyphenols and flavonoids content. The DPPH, FRAP, and TAC of the extracts revealed that CP, PT, and PP have a potent antioxidant effect compared to SL. MDA analysis revealed the same antioxidant activity as CP, PT and PP showed a minor MDA level. The egg albumin denaturation assay showed that IC50 of CP and PP was significantly higher than control (P < 0.05). In contrast, the Bovine Serum Albumin (BSA) results showed a nonsignificant effect (P > 0.05). Notably, SL extract was nonsignificant to control in both Egg Albumin and BSA. Furthermore, angiogenesis assay showed that SL at 50 µg/ml and PP at 100 µg/ml effectively reduced the number of blood vessels than control and showed a potent anti-angiogenic effect (2.7-fold and 2.5-fold, respectively, P < 0.05). No cytotoxicity on PBMC was reported for CP, PP, and PT up to 1000 µg/ml, whereas SL at 1000 µg/ml exhibit benign cytotoxicity (P < 0.0001). CONCLUSION: This study provided in vitro evidence supporting further evaluation on cancer cell lines and tumors in vivo.
Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Medicinas Tradicionales Africanas , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/prevención & control , Plantas Medicinales/química , Albúminas/química , Animales , Antiinflamatorios/química , Supervivencia Celular/efectos de los fármacos , Pollos , Humanos , Inflamación/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Ratas , Albúmina Sérica Bovina , TogoRESUMEN
eIF4E plays an important role in regulating tumor growth and angiogenesis, and eIF4E is highly expressed in a variety of lung cancer cell lines. siRNA eIF4E can significantly inhibit the proliferation of lung cancer cells, indicating that inhibition of eIF4E may become a novel anti-tumor target. In the previous study, we synthesized a series of small molecule compounds with the potential to inhibit eIF4E. Among them, the compound EGPI-1 significantly inhibited the proliferation of a variety of lung cancer cells such as A549, NCI-H460, NCI-H1650 and 95D without inhibiting the proliferation of HUVEC cells. Further studies found that EGPI-1 interfered with the eIF4E/eIF4G interaction and inhibited the phosphorylation of eIF4E in NCI-H460 cells. The results of flow cytometry showed that EGPI-1 induced apoptosis and G0/G1 cycle arrest in NCI-H460 cell. Interestingly, we also found that EGPI-1 induced autophagy and DNA damage in NCI-H460 cells. The mechanism results showed that EGPI-1 inhibited the Ras/MNK/ERK/eIF4E signaling pathway. Moreover, EGPI-1 inhibited tube formation of HUVECs, as well as inhibited the neovascularization of CAM, proving the anti-angiogenesis activity of EGPI-1. The NCI-H460 xenograft studies showed that EGPI-1 inhibited tumor growth and angiogenesis in vivo by regulating Ras/MNK/ERK/eIF4E pathway. Our studies proved that eIF4E was a novel target for regulating tumor growth, and the eIF4E/eIF4G interaction inhibitor EGPI-1 was promising to develop into a novel anti-lung cancer drug.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Compuestos de Bencilideno/farmacología , Factor 4E Eucariótico de Iniciación/antagonistas & inhibidores , Factor 4G Eucariótico de Iniciación/antagonistas & inhibidores , Hidrazinas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Tiazoles/farmacología , Células A549 , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Compuestos de Bencilideno/química , Compuestos de Bencilideno/uso terapéutico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Embrión de Pollo , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Hidrazinas/química , Hidrazinas/uso terapéutico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neovascularización Patológica/prevención & control , Transducción de Señal/efectos de los fármacos , Tiazoles/química , Tiazoles/uso terapéutico , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
An interaction between acute myeloid leukemia (AML) cells and endothelial cells in the bone marrow seems to play a critical role in chemosensitivity on leukemia treatment. The endothelial niche reportedly enhances the paracrine action of the soluble secretory proteins responsible for chemoresistance in a vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR-2) signaling pathway-dependent manner. To further investigate the contribution of VEGF-A/VEGFR-2 signaling to the chemoresistance of AML cells, a biochemical assay system in which the AML cells were cocultured with human endothelial EA.hy926 cells in a monolayer was developed. By coculture with EA.hy926 cells, this study revealed that the AML cells resisted apoptosis induced by the anticancer drug cytarabine. SU4312, a VEGFR-2 inhibitor, attenuated VEGFR-2 phosphorylation and VEGF-A/VEGFR-2 signaling-dependent endothelial cell migration; thus, this inhibitor was observed to block VEGF-A/VEGFR-2 signaling. Interestingly, this inhibitor did not reverse the chemoresistance. When VEGFR-2 was knocked out in EA.hy926 cells using the CRISPR-Cas9 system, the cytarabine-induced apoptosis of AML cells did not significantly change compared with that of wild-type cells. Thus, coculture-induced chemoresistance appears to be independent of VEGF-A/VEGFR-2 signaling. When the transwell, a coculturing device, separated the AML cells from the EA.hy926 cells in a monolayer, the coculture-induced chemoresistance was inhibited. Given that the migration of VEGF-A/VEGFR-2 signaling-dependent endothelial cells is necessary for the endothelial niche formation in the bone marrow, VEGF-A/VEGFR-2 signaling contributes to chemoresistance by mediating the niche formation process, but not to the chemoresistance of AML cells in the niche.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Citarabina/farmacología , Resistencia a Antineoplásicos/genética , Factor A de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Inhibidores de la Angiogénesis/farmacología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular , Movimiento Celular/efectos de los fármacos , Técnicas de Cocultivo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Regulación Leucémica de la Expresión Génica , Técnicas de Inactivación de Genes , Células HL-60 , Humanos , Indoles/farmacología , Células Jurkat , Células K562 , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Modelos Biológicos , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neovascularización Patológica/prevención & control , Fosforilación , Transducción de Señal , Células U937 , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/deficienciaRESUMEN
Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.