Designación, desarrollo y acceso de medicamentos huérfanos.

This article aims to sum up the most important ideas discussed during the online series of conferences about Designation, Development and Access to Orphan Drugs organized by the Spanish Centre of Network Research of Rare Diseases (CIBERER) the past 28th of October 2020, in which experts from different areas (institution, companies and research) talked about the designation process for orphan drugs, the great importance of this classification, and the advantages this implies for the researchers in terms of the study of new therapies and drug development, and for pharmaceutical companies in terms of economical protection.En este artículo se resumen las ideas más importantes que fueron tratadas en la jornada telemática de Designación, Desarrollo y Acceso de Medicamentos Huérfanos organizada por el Centro de Investigación en Red de Enfermedades Raras (CIBERER) el pasado 28 de octubre de 2020, jornada en la que expertos del área institucional, empresarial y científica nos hablaron del proceso de designación de un medicamento huérfano, la importancia de esta clasificación y las ventajas con relación al desarrollo de medicamentos para la comunidad investigadora dedicada al estudio de enfermedades raras, y en cuanto a protección económica para las empresas farmacéuticas

Evaluation of the anti-angiogenic potential of hydroxytyrosol derivatives

Angiogenesis, a process which allows the formation of new vessels from pre-existing ones, is an essential phenomenon for tumor survival since it allows cancer cells to obtain nutrients and oxygen. This explains the increasing interest showed by many groups of research and pharmaceutical companies to find compounds with potential to disrupt at least one of the steps within the angiogenic process. Hydroxytyrosol (3,4-dihydroxyphenyl ethanol) has been identified as the most important health-related phenolic compound of virgin olive oil because of its pleiotropic effects on multiple targets. In 2012, our group identified hydroxytyrosol as an anti-angiogenic compound able to inhibit several key steps in the angiogenic process. In the present study, the potential effects of six hydroxytyrosol derivatives are tested and compared with those exhibited by hydroxytyrosol by making use of several in vitro and in vivo assays. Results indicate that these are candidate new anti-angiogenic compounds with potential utility in anti-tumor and anti-angiogenic therapies.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech [Our experimental work is supported by grants BIO2014-56092-R (MINECO and FEDER) and P12-CTS-1507 (Andalusian Government and FEDER) and funds from group BIO-267 (Andalusian Government). The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain)]. This communication has the support of a travel grant

(-)-Oleacein and (-)-oleocanthal, two phenolic compounds present in Extra Virgin Olive Oil, inhibit angiogenesis

Phenolic compounds in the Mediterranean diet contribute to many of the health-related benefits accounted in this dietary choice. (-)-Oleocanthal and the less studied (-)-oleacein, are two phenolic compounds present in the Extra Virgin Olive Oil that have shown anti-tumoural effects both in vitro and in vivo. Among their effects on cancer, they could inhibit tumour cell migration and invasion, key processes also in angiogenesis, the process by which de novo blood vessels are formed. Herein, we explored the anti-angiogenic potential of (-)-oleocanthal and (-)-oleacein in a comparative study in in vitro experiments on endothelial cells, and in two in vivo models. (-)-Oleocanthal and (-)-oleacein affected endothelial viability in the micromolar range, as well as the formation of tubule-like structures by these cells, and their migration. Interestingly, only oleacein inhibited cell migration and induced apoptosis significantly. Regarding cellular signalling, both compounds were able to reduce the activation of the AKT and ERK1/2 pathways, which are related to survival and proliferation, respectively. Finally, both compounds showed anti-angiogenic activity in a zebrafish model of regeneration and in the chicken chorioallantoic membrane. Altogether, these results support the anti-angiogenic potential of (-)-oleocanthal and (-)-oleacein, and suggest that (-)-oleacein exerts more potent effects on endothelial cell migration and induction of apoptosis. Thus, we propose these two phenolic compounds, with a special focus on (-)-oleacein, as new candidates for clinical use as anti-cancer and anti-angiogenic agents. [Grants: PID2019-105010RB-I00 and RTI2018-098560-BC22 (Spanish Government), UMA18-FEDERJA-220, and PY20_00257 (Andalusian Government and FEDER). Funds from BIO 267 (Andalusian Government). CIBERER, CIBERCV].Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The Extra Virgin Olive Oil phenolic compounds () oleacein and () oleocanthal inhibit tumor cell autophagy

Es una comunicación a congreso internacional en formato póster.Our group has recently shown that the antitumor Extra Virgin Olive Oil phenolic compounds (—)oleocanthal and (—)oleacein also behave as antiangiogenic agents. Interestingly, it has been described that phenolic compounds found in the Mediterranean diet affect the autophagy pathway. Based on this background, we studied the modulatory effects of (—)oleocanthal and (—)oleacein on tumor cell autophagy. Methodologically, the tumor cell lines MDAMB231, MCF7 and HT1080 cell lines were used in in vitro cellular and molecular studies of the autophagy flux and key mediators of this process, and High Content Screening (HCS) System using Perkin Elmer Operetta for single-cell analysis was performed in these cells. Interestingly, (—)oleocanthal and (—)oleacein repressed the autophagy flux of MDAMB231 and MCF7 submitted to autophagy inducing conditions (severe starving) at doses in the low micromolar range. In addition, key autophagy mediators, like LC3 or WIPI2 proteins, were dramatically reduced in the same settings, as seen in immunohistochemical studies. Furthermore, preliminary results of HCS in tumor cells revealed depletory effects on autophagy by using specifics dyes for this process at the single-cell level. Altogether, our results point to a drastic inhibitory effect of (—)oleocanthal and (—)oleacein on tumor cell autophagy at low doses.[Grants: PID2022-138181OB-I00, PID2019-105010RB-I00 and RTI2018-098560-BC22 (Spanish Government), UMA18-FEDERJA-220, and PY20_00257 (Andalusian Government and FEDER). Funds from BIO 267 (Andalusian Government) M.B. is supported by “Juan de la Cierva – Incorporation Program” (IJC2018-037657-I), Spanish Ministry of Science and Innovation, Spain.]. Supported with a a help from the «II Plan Propio de Investigación, Transferencia y Divulgación Científica de la UMA», Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The synthetic molecule stauprimide impairs cell growth and migration in triple-negative breast cancer

Stauprimide, a semi-synthetic derivative of staurosporine, is known mainly for its potent differentiation-enhancing properties in embryonic stem cells. Here, we studied the effects of stauprimide in cell growth and migration of triple-negative breast cancer cells in vitro, evaluating its potential antitumoral activity in an orthotopic mouse model of breast cancer in vivo. Our results from survival curves, EdU incorporation, cell cycle analysis and annexin-V detection in MDA-MB-231 cells indicated that stauprimide inhibited cell proliferation, arresting cell cycle in G2/M without induction of apoptosis. A decrease in the migratory capability of MDA-MB-231 was also assessed in response to stauprimide. In this work we pointed to a mechanism of action of stauprimide involving the modulation of ERK1/2, Akt and p38 MAPK signalling pathways, and the downregulation of MYC in MDA-MB-231 cells. In addition, orthotopic MDA-MB-231 xenograft and 4T1 syngeneic models suggested an effect of stauprimide in vivo, increasing the necrotic core of tumors and reducing metastasis in lung and liver of mice. Together, our results point to the promising role of stauprimide as a putative therapeutic agent in triple-negative breast cancer.MRI experiments were performed in the ICTS “NANBIOSIS”, more specifically in the U28 Unit at the Andalusian Centre for Nanomedicine & Biotechnology (BIONAND). Cell cultures were performed in the Cell Culture Service at the Central Support Services of Research (SCAI) of the University of Málaga. // Partial funding for open access charge: Universidad de Málaga / CBUA

A comparative study of the antiangiogenic activity of hydroxytyrosyl alkyl ethers

Versión preprint del manuscrito de los autores, publicado finalmente en: Food Chemistry 333 (2020) 127476 con DOI: 10.1016/j.foodchem.2020.127476The phenolic compound hydroxytyrosol and its derivatives are responsible for some of the health benefits of the intake of virgin olive oil, having shown antiangiogenic properties. In this study, we explored the antiangiogenic potential of six synthetic hydroxytyrosyl alkyl ethers (HT C1, C2, C4, C6, C8 and C12). Our results showed that all compounds affected endothelial cell viability in vitro at low micromolar doses. In addition, compounds HT C1, C2, C4 and C6 inhibited endothelial cell migration and formation of tubular-like structures. In these assays, hydroxytyrosyl hexyl ether (HT C6) exhibited the most potent inhibitory activity in vitro, activating as well apoptosis in endothelial cells. Furthermore, the antiangiogenic activity of HT C6 was confirmed in vivo in the chick chorioallantoic membrane assay. Hence, we present hydroxytyrosol synthetic derivative HT C6 as a new antiangiogenic compound and as a good candidate for an antiangiogenic drug in the treatment of angiogenesisdependent diseases.This work was supported by the Spanish Ministry of Science, Innovation and Universities (grants AGL2007-66373 and PID2019- 105010RB-I00), Andalusian Government and FEDER (P12-CTS-1507, UMA18-FEDERJA-220 and funds from group BIO 267), as well as funds from the University of Málaga (“Plan Propio de Investigación y Transferencia”). The “CIBER de Enfermedades Raras” and “CIBER de Enfermedades Cardiovasculares” are initiatives from the ISCIII (Spain). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript

Antiangiogenic Phytochemicals Constituent of Diet as Promising Candidates for Chemoprevention of Cancer.

Despite the extensive knowledge on cancer nature acquired over the last years, the high incidence of this disease evidences a need for new approaches that complement the clinical intervention of tumors. Interestingly, many types of cancer are closely related to dietary habits associated with the Western lifestyle, such as low fruit and vegetable intake. Recent advances around the old-conceived term of chemoprevention highlight the important role of phytochemicals as good candidates for the prevention or treatment of cancer. The potential to inhibit angiogenesis exhibited by many natural compounds constituent of plant foods makes them especially interesting for their use as chemopreventive agents. Here, we review the antitumoral potential, with a focus on the antiangiogenic effects, of phenolic and polyphenolic compounds, such as quercetin or myricetin; terpenoids, such as ursolic acid or kahweol; and anthraquinones from Aloe vera, in different in vitro and in vivo assays, and the available clinical data. Although clinical trials have failed to assess the preventive role of many of these compounds, encouraging preclinical data support the efficacy of phytochemicals constituent of diet in the prevention and treatment of cancer, but a deeper understanding of their mechanisms of action and better designed clinical trials are urgently needed

Pyroptosis Modulators: New Insights of Gasdermins in Health and Disease

Pyroptosis is an inflammation-dependent type of cell death that has been in the spotlight for the scientific community in the last few years. Crucial players in the process of pyroptosis are the members of the gasdermin family of proteins, which have been parallelly studied. Upon induction of pyroptosis, gasdermins suffer from structural changes leading to the formation of pores in the membrane that subsequently cause the release of pro-inflammatory contents. Recently, it has been discovered that oxidation plays a key role in the activation of certain gasdermins. Here, we review the current knowledge on pyroptosis and human gasdermins, focusing on the description of the different members of the family, their molecular structures, and their influence on health and disease directly or non-directly related to inflammation. Noteworthy, we have focused on the existing understanding of the role of this family of proteins in cancer, which could translate into novel promising strategies aimed at benefiting human health. In conclusion, the modulation of pyroptosis and gasdermins by natural and synthetic compounds through different mechanisms, including modification of the redox state of cells, has been proven effective and sets precedents for future therapeutic strategies