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1دورية أكاديمية
المؤلفون: Verónica Alonso-Pérez, Vanessa Hernández, Marco A. Calzado, Alba Vicente-Blázquez, Consuelo Gajate, Rafael Soler-Torronteras, Kathleen DeCicco-Skinner, Angels Sierra, Faustino Mollinedo
المصدر: Biomedicine & Pharmacotherapy, Vol 171, Iss , Pp 116149- (2024)
مصطلحات موضوعية: Metastatic organ colonization, Metastasis, Angiogenesis, Antitumor activity, Edelfosine, Alkylphospholipid analog, Therapeutics. Pharmacology, RM1-950
الوصف: Metastasis is the leading cause of cancer mortality. Metastatic cancer is notoriously difficult to treat, and it accounts for the majority of cancer-related deaths. The ether lipid edelfosine is the prototype of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs, and its antitumor activity involves lipid raft reorganization. In this study, we examined the effect of edelfosine on metastatic colonization and angiogenesis. Using non-invasive bioluminescence imaging and histological examination, we found that oral administration of edelfosine in nude mice significantly inhibited the lung and brain colonization of luciferase-expressing 435-Lung-eGFP-CMV/Luc metastatic cells, resulting in prolonged survival. In metastatic 435-Lung and MDA-MB-231 breast cancer cells, we found that edelfosine also inhibited cell adhesion to collagen-I and laminin-I substrates, cell migration in chemotaxis and wound-healing assays, as well as cancer cell invasion. In 435-Lung and other MDA-MB-435-derived sublines with different organotropism, edelfosine induced G2/M cell cycle accumulation and apoptosis in a concentration- and time-dependent manner. Edelfosine also inhibited in vitro angiogenesis in human and mouse endothelial cell tube formation assays. The antimetastatic properties were specific to cancer cells, as edelfosine had no effects on viability in non-cancerous cells. Edelfosine accumulated in membrane rafts and endoplasmic reticulum of cancer cells, and membrane raft-located CD44 was downregulated upon drug treatment. Taken together, this study highlights the potential of edelfosine as an attractive drug to prevent metastatic growth and organ colonization in cancer therapy. The raft-targeted drug edelfosine displays a potent activity against metastatic organ colonization and angiogenesis, two major hallmarks of tumor malignancy.
وصف الملف: electronic resource
العلاقة: http://www.sciencedirect.com/science/article/pii/S0753332224000301Test; https://doaj.org/toc/0753-3322Test
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2دورية أكاديمية
المؤلفون: EL-Habib Dakir, Consuelo Gajate, Faustino Mollinedo
المصدر: Biomedicine & Pharmacotherapy, Vol 167, Iss , Pp 115436- (2023)
مصطلحات موضوعية: Edelfosine, Alkylphospholipid analog, MPAKT transgenic animal model, Xenograft animal model, Endoplasmic reticulum, Prostate cancer, Therapeutics. Pharmacology, RM1-950
الوصف: Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. While the five-year survival in local and regional prostate cancer is higher than 99%, it falls to about 28% in advanced metastatic prostate cancer. The ether lipid edelfosine is considered the prototype of a family of promising antitumor drugs collectively named as alkylphospholipid analogs. Here, we found that edelfosine was the most potent alkylphospholipid analog in inducing apoptosis in three different human prostate cancer cell lines (LNCaP, PC3, and DU145) with distinct androgen dependency, and differing in tumor suppressor phosphatase and tensin homolog (PTEN) and p53 status. Edelfosine accumulated in the endoplasmic reticulum of prostate cancer cells, leading to endoplasmic reticulum stress and cell death in the three prostate cancer cells. Inhibition of autophagy potentiated the pro-apoptotic activity of edelfosine in LNCaP and PC3 cells, where autophagy was induced as a survival response. Edelfosine induced a slight and transient inhibition of AKT in PTEN-negative LNCaP and PC3 cells, but not in PTEN-positive DU145 cells. Daily oral administration of edelfosine in murine prostate restricted AKT kinase transgenic mice, expressing active AKT in a prostate-specific manner, and in a DU145 xenograft mouse model resulted in significant tumor regression and apoptosis in tumor cells. Taken together, these results show a significant in vitro and in vivo antitumor activity of edelfosine against prostate cancer, and highlight the endoplasmic reticulum as a novel and promising therapeutic target in prostate cancer.
وصف الملف: electronic resource
العلاقة: http://www.sciencedirect.com/science/article/pii/S0753332223012349Test; https://doaj.org/toc/0753-3322Test
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3دورية أكاديمية
المؤلفون: Rósula García-Navas, Consuelo Gajate, Faustino Mollinedo
المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
الوصف: Abstract Human neutrophils constitutively express high amounts of arginase-1, which depletes arginine from the surrounding medium and downregulates T-cell activation. Here, we have found that neutrophil arginase-1, released from activated human neutrophils or dead cells, induced apoptosis in cancer cells through an endoplasmic reticulum (ER) stress pathway. Silencing of PERK in cancer cells prevented the induction of ER stress and apoptosis. Arginase inhibitor Nω-hydroxy-nor-arginine inhibited apoptosis and ER stress response induced by conditioned medium from activated neutrophils. A number of tumor cell lines, derived from different tissues, were sensitive to neutrophil arginase-1, with pancreatic, breast, ovarian and lung cancer cells showing the highest sensitivity. Neutrophil-released arginase-1 and arginine deprivation potentiated the antitumor action against pancreatic cancer cells of the ER-targeted antitumor alkylphospholipid analog edelfosine. Our study demonstrates the involvement of neutrophil arginase-1 in cancer cell killing and highlights the importance and complex role of neutrophils in tumor surveillance and biology.
وصف الملف: electronic resource
العلاقة: https://doaj.org/toc/2045-2322Test
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4دورية أكاديمية
المصدر: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 2025-2044 (2021)
مصطلحات موضوعية: indolesulfonamides, antimitotic, total polar surface area, structure–activity relationships, colchicine-site, Therapeutics. Pharmacology, RM1-950
الوصف: Searching for improved indolesulfonamides with higher polarities, 45 new analogues with modifications on the sulfonamide nitrogen, the methoxyaniline, and/or the indole 3-position were synthesised. They show submicromolar to nanomolar antiproliferative IC50 values against four human tumour cell lines and they are not P-glycoprotein substrates as their potencies against HeLa cells did not improve upon cotreatment with multidrug resistance (MDR) inhibitors. The compounds inhibit tubulin polymerisation in vitro and in cells, thus causing a mitotic arrest followed by apoptosis as shown by cell cycle distribution studies. Molecular modelling studies indicate binding at the colchicine site. Methylated sulfonamides were more potent than those with large and polar substitutions. Amide, formyl, or nitrile groups at the indole 3-position provided drug-like properties for reduced toxicity, with Polar Surface Areas (PSA) above a desirable 75 Å2. Nitriles 15 and 16 are potent polar analogues and represent an interesting class of new antimitotics.
وصف الملف: electronic resource
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5دورية أكاديمية
المؤلفون: Faustino Mollinedo, Consuelo Gajate
المصدر: Journal of Lipid Research, Vol 61, Iss 5, Pp 611-635 (2020)
مصطلحات موضوعية: cholesterol • cholesterol-rich membrane domains • IGF system • PI3K/AKT signaling • Fas/CD95 • death receptor • CASMER • raft targeting, Biochemistry, QD415-436
الوصف: Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to regulatory or effector molecules. Thus, lipid rafts serve as sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels of intracellular cholesterol and lipid rafts than their normal non-tumorigenic counterparts. Many signal transduction processes involved in cancer development (insulin-like growth factor system and phosphatidylinositol 3-kinase-AKT) and metastasis [cluster of differentiation (CD)44] are dependent on or modulated by lipid rafts. Additional proteins playing an important role in several malignant cancers (e.g., transmembrane glycoprotein mucin 1) are also being detected in association with lipid rafts, suggesting a major role of lipid rafts in tumor progression. Conversely, lipid rafts also serve as scaffolds for the recruitment and clustering of Fas/CD95 death receptors and downstream signaling molecules leading to cell death-promoting raft platforms. The partition of death receptors and downstream signaling molecules in aggregated lipid rafts has led to the formation of the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER, which leads to apoptosis amplification and can be pharmacologically modulated. These death-promoting rafts can be viewed as a linchpin from which apoptotic signals are launched. In this review, we discuss the involvement of lipid rafts in major signaling processes in cancer cells, including cell survival, cell death, and metastasis, and we consider the potential of lipid raft modulation as a promising target in cancer therapy.
وصف الملف: electronic resource
العلاقة: http://www.sciencedirect.com/science/article/pii/S0022227520436132Test; https://doaj.org/toc/0022-2275Test
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6دورية أكاديمية
المؤلفون: Irene Mollinedo-Gajate, PhD, Felipe Villar-Álvarez, MD, PhD, María de los Ángeles Zambrano-Chacón, MD, Laura Núñez-García, MD, Laura de la Dueña-Muñoz, MD, Carlos López-Chang, MD, Miguel Górgolas, MD, PhD, Alfonso Cabello, MD, PhD, Olga Sánchez-Pernaute, MD, PhD, Fredeswinda Romero-Bueno, MD, PhD, Álvaro Aceña, MD, PhD, Nicolás González-Mangado, MD, PhD, Germán Peces-Barba, MD, PhD, Faustino Mollinedo, PhD
المصدر: Critical Care Explorations, Vol 3, Iss 2, p e0346 (2021)
مصطلحات موضوعية: Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
الوصف: Objectives:. This study aims to determine similarities and differences in clinical characteristics between the patients from two waves of severe acute respiratory syndrome coronavirus-2 infection at the time of hospital admission, as well as to identify risk biomarkers of coronavirus disease 2019 severity. Design:. Retrospective observational study. Setting:. A single tertiary-care center in Madrid. Patients:. Coronavirus disease 2019 adult patients admitted to hospital from March 4, 2020, to March 25, 2020 (first infection wave), and during July 18, 2020, and August 20, 2020 (second infection wave). Interventions:. Treatment with a hospital-approved drug cocktail during hospitalization. Measurements and Main Results:. Demographic, clinical, and laboratory data were compared between the patients with moderate and critical/fatal illness across both infection waves. The median age of patients with critical/fatal coronavirus disease 2019 was 67.5 years (interquartile range, 56.75–78.25 yr; 64.5% male) in the first wave and 59.0 years (interquartile range, 48.25–80.50 yr; 70.8% male) in the second wave. Hypertension and dyslipidemia were major comorbidities in both waves. Body mass index over 25 and presence of bilateral pneumonia were common findings. Univariate logistic regression analyses revealed an association of a number of blood parameters with the subsequent illness progression and severity in both waves. However, some remarkable differences were detected between both waves that prevented an accurate extrapolation of prediction models from the first wave into the second wave. Interleukin-6 and d-dimer concentrations at the time of hospital admission were remarkably higher in patients who developed a critical/fatal condition only during the first wave (p < 0.001), although both parameters significantly increased with disease worsening in follow-up studies from both waves. Multivariate analyses from wave 1 rendered a predictive signature for critical/fatal illness upon hospital admission that comprised six blood biomarkers: neutrophil-to-lymphocyte ratio (≥ 5; odds ratio, 2.684 [95% CI, 1.143–6.308]), C-reactive protein (≥ 15.2 mg/dL; odds ratio, 2.412 [95% CI, 1.006–5.786]), lactate dehydrogenase (≥ 411.96 U/L; odds ratio, 2.875 [95% CI, 1.229–6.726]), interleukin-6 (≥ 78.8 pg/mL; odds ratio, 5.737 [95% CI, 2.432–13.535]), urea (≥ 40 mg/dL; odds ratio, 1.701 [95% CI, 0.737–3.928]), and d-dimer (≥ 713 ng/mL; odds ratio, 1.903 [95% CI, 0.832–4.356]). The predictive accuracy of the signature was 84% and the area under the receiver operating characteristic curve was 0.886. When the signature was validated with data from wave 2, the accuracy was 81% and the area under the receiver operating characteristic curve value was 0.874, albeit most biomarkers lost their independent significance. Follow-up studies reassured the importance of monitoring the biomarkers included in the signature, since dramatic increases in the levels of such biomarkers occurred in critical/fatal patients over disease progression. Conclusions:. Most parameters analyzed behaved similarly in the two waves of coronavirus disease 2019. However, univariate logistic regression conducted in both waves revealed differences in some parameters associated with poor prognosis in wave 1 that were not found in wave 2, which may reflect a different disease stage of patients on arrival to hospital. The six-biomarker predictive signature reported here constitutes a helpful tool to classify patient’s prognosis on arrival to hospital.
وصف الملف: electronic resource
العلاقة: http://journals.lww.com/10.1097/CCE.0000000000000346Test; https://doaj.org/toc/2639-8028Test
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7دورية أكاديمية
المؤلفون: Consuelo Gajate, Odile Gayet, Nicolas A. Fraunhoffer, Juan Iovanna, Nelson Dusetti, Faustino Mollinedo
المصدر: Cancers, Vol 13, Iss 23, p 6124 (2021)
مصطلحات موضوعية: pancreatic cancer stem cell, pancreatic cancer spheroid, endoplasmic reticulum, endoplasmic reticulum targeting, autophagy, pancreatic cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+CD24+EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0/G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.
وصف الملف: electronic resource
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8دورية أكاديمية
المؤلفون: Faustino Mollinedo, Consuelo Gajate
المصدر: Cancers, Vol 13, Iss 16, p 4173 (2021)
مصطلحات موضوعية: endoplasmic reticulum stress, endoplasmic reticulum targeting, pancreatic cancer, cancer therapy, alkylphospholipid analog, edelfosine, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.
وصف الملف: electronic resource
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9دورية أكاديمية
المصدر: Parasites & Vectors, Vol 10, Iss 1, Pp 1-10 (2017)
مصطلحات موضوعية: PKB/AKT, RAC/AKT-like, Therapeutic target, Leishmania, Leishmania donovani, Trypanosomatid, Infectious and parasitic diseases, RC109-216
الوصف: Abstract Background Leishmaniasis is one of the world’s most neglected diseases caused by at least 20 different species of the protozoan parasite Leishmania. Although new drugs have become recently available, current therapy for leishmaniasis is still unsatisfactory. A subgroup of serine/threonine protein kinases named as related to A and C protein kinases (RAC), or protein kinase B (PKB)/AKT, has been identified in several organisms including Trypanosoma cruzi parasites. PKB/AKT plays a critical role in mammalian cell signaling promoting cell survival and is a major drug target in cancer therapy. However, the role of protozoan parasitic PKB/AKT remains to be elucidated. Results We have found that anti-human AKT antibodies recognized a protein of about 57 kDa in Leishmania spp. parasites. Anti-human phospho-AKT(Thr308) antibodies identified a protein in extracts from Leishmania spp. that was upregulated following parasite exposure to stressful conditions, such as nutrient deprivation or heat shock. Incubation of AKT inhibitor X with Leishmania spp. promastigotes under stressful conditions or with Leishmania-infected macrophages led to parasite cell death. We have identified and cloned a novel gene from Leishmania donovani named Ld-RAC/AKT-like gene, encoding a 510-amino acid protein of approximately 57.6 kDa that shows a 26.5% identity with mammalian AKT1. Ld-RAC/AKT-like protein contains major mammalian PKB/AKT hallmarks, including the typical pleckstrin, protein kinase and AGC kinase domains. Unlike mammalian AKT that contains key phosphorylation sites at Thr308 and Ser473 in the activation loop and hydrophobic motif, respectively, Ld-RAC/AKT-like protein has a Thr residue in both motifs. By domain sequence comparison, we classified AKT proteins from different origins in four major subcategories that included different parasites. Conclusions Our data suggest that Ld-RAC/AKT-like protein represents a Leishmania orthologue of mammalian AKT involved in parasite stress response and survival, and therefore could become a novel therapeutic and druggable target in leishmaniasis therapy. In addition, following comparative sequence analyses, we found the RAC/AKT-like proteins from Leishmania constitute a subgroup by themselves within a general AKT-like protein family.
وصف الملف: electronic resource
العلاقة: http://link.springer.com/article/10.1186/s13071-017-2379-yTest; https://doaj.org/toc/1756-3305Test
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10دورية أكاديمية
المؤلفون: Faustino Mollinedo, Consuelo Gajate
المصدر: Pharmaceutics, Vol 13, Iss 5, p 763 (2021)
مصطلحات موضوعية: mitochondria, cholesterol, lipid raft, mitochondrial permeability transition pore, alkylphospholipid analog, edelfosine, Pharmacy and materia medica, RS1-441
الوصف: The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with cholesterol-rich lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine induces apoptosis in a number of hematological cancer cells by recruiting death receptors and downstream apoptotic signaling into lipid rafts, whereas it promotes apoptosis in solid tumor cells through an ER stress response. Edelfosine-induced apoptosis, mediated by lipid rafts and/or ER, requires the involvement of a mitochondrial-dependent step to eventually elicit cell death, leading to the loss of mitochondrial membrane potential, cytochrome c release and the triggering of cell death. The overexpression of Bcl-2 or Bcl-xL blocks edelfosine-induced apoptosis. Edelfosine induces the redistribution of lipid rafts from the plasma membrane to the mitochondria. The pro-apoptotic action of edelfosine on cancer cells is associated with the recruitment of F1FO–ATP synthase into cholesterol-rich lipid rafts. Specific inhibition of the FO sector of the F1FO–ATP synthase, which contains the membrane-embedded c-subunit ring that constitutes the mitochondrial permeability transcription pore, hinders edelfosine-induced cell death. Taking together, the evidence shown here suggests that the ether lipid edelfosine could modulate cell death in cancer cells by direct interaction with mitochondria, and the reorganization of raft-located mitochondrial proteins that critically modulate cell death or survival. Here, we summarize and discuss the involvement of mitochondria in the antitumor action of the ether lipid edelfosine, pointing out the mitochondrial targeting of this drug as a major therapeutic approach, which can be extrapolated to other alkylphospholipid analogs. We also discuss the involvement of cholesterol transport and cholesterol-rich lipid rafts in the interactions between the organelles as well as in the role of mitochondria in the regulation of apoptosis in cancer cells and cancer therapy.
وصف الملف: electronic resource
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