Biomedical subjects

Ana R Quesada

Publications and source records attributed to Ana R Quesada.

10 recordsLinked to original sources

PubMed2006

Hyperforin: more than an antidepressant bioactive compound?

Hyperforin is a lipophilic compound that is present in great amounts in St. John's wort and that has been described as the main responsible for the antidepressant effects of this medicinal plant. In the last few years, evidence has accumulated pointing to other different effects of hyperforin with potential pharmacological interest. They include other neurological effects, effects on inflammation, as well as antibacterial, antitumoral and antiangiogenic effects.

Angiogenesis Inhibitors↗

PubMed2006

Anti-angiogenic drugs: from bench to clinical trials.

Angiogenesis, the generation of new capillaries through a process of pre-existing microvessel sprouting, is under stringent control and normally occurs only during embryonic and post-embryonic development, reproductive cycle, and wound repair. However, in many pathological conditions (solid tumor progression, metastasis, diabetic retinopathy, hemangioma, arthritis, psoriasis and atherosclerosis among others), the disease appears to be associated with persistent upregulated angiogenesis. The development of specific anti-angiogenic agents arises as an attractive therapeutic approach for the treatment of cancer and other angiogenesis-dependent diseases. The formation of new blood vessels is a complex multi-step process. Endothelial cells resting in the parent vessels are activated by an angiogenic signal and stimulated to synthesize and release degradative enzymes allowing endothelial cells to migrate, proliferate and finally differentiate to give rise to capillary tubules. Any of these steps may be a potential target for pharmacological intervention. In spite of the disappointing results obtained initially in clinical trials with anti-angiogenic drugs, recent reports with positive results in phases II and III trials encourage expectations in their therapeutic potential. This review discusses the current approaches for the discovery of new compounds that inhibit angiogenesis, with emphasis on the clinical developmental status of anti-angiogenic drugs.

Angiogenesis Inhibitors↗

PubMed2005

Hyperforin, a bio-active compound of St. John's Wort, is a new inhibitor of angiogenesis targeting several key steps of the process.

Hyperforin, a phloroglucinol derivative found in St. John's wort related mainly to its antidepressant effects, has been reported recently to induce apoptosis in tumour cells and to inhibit cancer invasion and metastasis. We show that hyperforin inhibits angiogenesis in vitro in bovine aortic endothelial cells and in vivo in the chorioallantoic membrane assay. In a variety of experimental systems representing the sequential events of the angiogenic process, hyperforin treatment of endothelial cells resulted in strong inhibitory effects. Hyperforin inhibited the growth of endothelial cells in culture. Capillary tube formation on Matrigel was abrogated completely by addition of hypeforin at the low micromolar range. Hyperforin also exhibited a clear inhibitory effect on the invasive capabilities of endothelial cells. Zymographic assays showed that hyperforin treatment produced a complete inhibition of urokinase and a remarkable inhibition of matrix metalloproteinase 2. Our data indicates that hyperforin is a compound that interferes with key events in angiogenesis, confirming the recent and growing evidence about a potential role of this compound in cancer and metastasis inhibition and making it a promising drug for further evaluation in the treatment of angiogenesis-related pathologies.

3T3 Cells↗

PubMed2005

Hypericin in the dark inhibits key steps of angiogenesis in vitro.

Photoactivated hypericin has a potent cytotoxic effect over a wide range of cells. However, very recently hypericin has been shown to have antitumoral and antimetastatic effects in the dark. The aim of this study was to test whether hypericin in the dark affects angiogenesis. Different in vitro assays were used to study the potential effects of this compound on key steps of angiogenesis, namely, a colorimetric assay of cell proliferation/viability, a tubular formation on Matrigel assay, zymographic assays for gelatinases and urokinase, a wound assay for migration and a fluorometric assay for invasion through Matrigel. In this report, we show for the first time that hypericin kept in the dark inhibits several key steps of the angiogenic process, namely, bovine endothelial cell proliferation, formation of tubular-like structures on Matrigel, migration and invasion, as well as extracellular matrix degrading urokinase.

Angiogenesis Inhibitors↗

PubMed2004

Effects of ursolic acid on different steps of the angiogenic process.

Ursolic acid is a triterpenoid with pleiotropic biological effects. In this report, we study the effects of ursolic acid on different key steps of angiogenesis. Our results show that ursolic acid is able to inhibit key steps of angiogenesis in vitro, including endothelial cell proliferation, migration, and differentiation. At the same time, it seems to stimulate other key steps of angiogenesis, such as extracellular matrix degradation by MMP-2 and urokinase. Although ursolic acid can inhibit in vivo angiogenesis in the CAM assay, the different signs of the effects it causes on different steps of angiogenesis force one to be cautious concerning its anti-angiogenic potential.

Animals↗

PubMed2004

Study of puupehenone and related compounds as inhibitors of angiogenesis.

Puupehenone, a sesquiterpene produced by certain sponges, was selected in the course of a blind screening for new potential inhibitors of angiogenesis. In our study, we compare the potential anti-angiogenic activities of puupehenone and another 11 related compounds that were either natural products from marine origin or their synthetic derivatives. The effects of these compounds were determined with cell growth and differentiation assays on bovine aorta endothelial cells. Our results show that these compounds are weak inhibitors to cell growth and are not selective for endothelial cells. However, contrary to cell growth, the differentiation of endothelial cells into tubular structures was completely inhibited by 7 of these compounds at concentrations equal or lower than 3 microM. Three of these compounds, isozonarol, 8-epipuupehedione and 8 epi-9,11-dihydropuupehedione, completely inhibited the in vivo angiogenesis in the CAM assay at doses equal or lower than 30 nmol/egg. Further characterisation showed that these 3 terpenes also inhibited endothelial cell production of urokinase and invasion. One compound (8-epipuupehedione) inhibited endothelial cell migration in a dose-dependent manner. The anti-angiogenic properties of the selected compounds, the simplicity of their structures and the feasibility of their synthesis make them attractive drugs for further evaluation in the treatment of angiogenesis-related pathologies.

Angiogenesis Inhibitors↗

PubMed2003

An in vitro evaluation of the effects of homocysteine thiolactone on key steps of angiogenesis and tumor invasion.

Homocysteine thiolactone is a highly reactive homocysteine derivative that can react easily with proteins. Protein homocysteinylation has been suggested as a possible mechanism underlying the pathological consequences of impaired homocysteine metabolism. Homocysteine inhibits key steps of angiogenesis and tumor invasion. It can be hypothesized that homocysteine thiolactone could mimic the described anti-angiogenic and anti-invasive effects of homocysteine. Therefore, we studied the effects of homocysteine thiolactone on different key steps of angiogenesis and tumor invasion, using model endothelial and tumor cell lines. This study demonstrates that homocysteine thiolactone, in high contrast to homocysteine, is not an anti-angiogenic compound. Furthermore, our results suggest that homocysteine thiolactone could behave as a pro-angiogenic compound.

Angiogenesis Inducing Agents↗

PubMed2003

Homocysteine is a potent inhibitor of human tumor cell gelatinases.

Extracellular matrix-degrading gelatinases are mainly involved in tumor invasion and metastasis. Previous experimental data from our group and others suggested that homocysteine could have a potential modulatory role on the proteolytic balance at the extracellular matrix. Therefore, we studied the effects of homocysteine on extracellular matrix-degrading proteases using model human tumor cell lines and a combination of in vitro fluorogenic assay and zymographic techniques. Homocysteine is shown to be the thiol compound with the most potent inhibitory activity on matrix metalloproteinase 9. Zymographies reveal that matrix metalloproteinase 2 is, at least, as sensitive to inhibition by homocysteine as matrix metalloproteinase 9 is. This study opens new ways to the potential pharmacological use of thiol compounds.

Culture Media, Conditioned↗

PubMed2003

A modified chorioallantoic membrane assay allows for specific detection of endothelial apoptosis induced by antiangiogenic substances.

Current in vivo angiogenesis assays allow for the assessment of vascular growth inhibition induced by a test substance, but they usually do not provide information about the mechanisms underlying such an inhibition. A potential antiangiogenic mechanism is the triggering of endothelial apoptosis in the growing vessels. Apoptogenic substances can be of interest for antiangiogenic therapy specially if they specifically perform their action on the angiogenic endothelium. We have developed a modification of the chorioallantoic membrane (CAM) assay using embryos of quail ( Coturnix coturnix japonica ). This novel assay allows to elucidate whether an antiangiogenic substance is specifically triggering an apoptotic response in endothelial cells. We have used a quail-specific monoclonal endothelial marker (QH1), a standard TUNEL technique of apoptotic cell labelling together with a general nuclear counterstaining with propidium iodide. Through laser confocal microscopy, paraffin sections of chorioallantoic membranes treated with test substances are stained in three colours: red for normal cell nuclei, yellow-green for apoptotic nuclei and blue for endothelial cells and endothelial progenitors. In a test experience, our assay showed significant differences in the apoptogenic properties of two antiangiogenic substances, camptothecin and aeroplysinin-1.

Acetonitriles↗

PubMed2001

Antiangiogenic activity of aeroplysinin-1, a brominated compound isolated from a marine sponge.

(+)-aeroplysinin-1, an antibacterial brominated compound produced by certain sponges, was selected during a blind high-throughput screening for new potential antiangiogenic compounds obtained from marine organisms. In a variety of experimental systems, representing the sequential events of the angiogenic process, aeroplysinin-1 treatment of endothelial cells resulted in strong inhibitory effects. Aeroplysinin-1 inhibited the growth of endothelial cells in culture and induced endothelial cell apoptosis. Capillary tube formation on Matrigel was completely abrogated by addition of aeroplysinin-1 at the low micromolar range. Aeroplysinin-1 also exhibited a clear inhibitory effect on the migration capabilities of endothelial cells. Zymographic assays showed that aeroplysinin-1 treatment produced a decrease in the concentration of matrix metalloproteinase-2 and urokinase in conditioned medium from endothelial cells. Finally, aeroplysinin-1 exhibited a dose-dependent inhibitory effect on the in vivo chorioallantoic membrane assay, showing potent apoptosis-inducing activity in the developing endothelium. The in vivo inhibition of angiogenesis by aeroplysinin-1 was confirmed by the Matrigel plug assay. Together, our data indicate that aeroplysinin-1 is a compound that interferes with key events in angiogenesis, making it a promising drug for further evaluation in the treatment of angiogenesis-related pathologies.

Acetonitriles↗