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Scientific Reports Oct 2016eEF1A2 is one of the isoforms of the alpha subunit of the eukaryotic Elongation Factor 1. It is overexpressed in human tumors and is endowed with oncogenic properties,...
eEF1A2 is one of the isoforms of the alpha subunit of the eukaryotic Elongation Factor 1. It is overexpressed in human tumors and is endowed with oncogenic properties, favoring tumor cell proliferation while inhibiting apoptosis. We demonstrate that plitidepsin, an antitumor agent of marine origin that has successfully completed a phase-III clinical trial for multiple myeloma, exerts its antitumor activity by targeting eEF1A2. The drug interacts with eEF1A2 with a K of 80 nM and a target residence time of circa 9 min. This protein was also identified as capable of binding [C]-plitidepsin in a cell lysate from K-562 tumor cells. A molecular modelling approach was used to identify a favorable binding site for plitidepsin at the interface between domains 1 and 2 of eEF1A2 in the GTP conformation. Three tumor cell lines selected for at least 100-fold more resistance to plitidepsin than their respective parental cells showed reduced levels of eEF1A2 protein. Ectopic expression of eEF1A2 in resistant cells restored the sensitivity to plitidepsin. FLIM-phasor FRET experiments demonstrated that plitidepsin localizes in tumor cells sufficiently close to eEF1A2 as to suggest the formation of drug-protein complexes in living cells. Altogether, our results strongly suggest that eEF1A2 is the primary target of plitidepsin.
Topics: Animals; Antineoplastic Agents; Binding Sites; Cell Line, Tumor; Cell Proliferation; Depsipeptides; HeLa Cells; Humans; Multiple Myeloma; Peptide Elongation Factor 1; Peptides, Cyclic; Protein Domains; Rabbits
PubMed: 27713531
DOI: 10.1038/srep35100 -
Science (New York, N.Y.) Feb 2021Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.
Topics: Adenosine Monophosphate; Alanine; Animals; Antiviral Agents; COVID-19; Coronavirus Nucleocapsid Proteins; Depsipeptides; Drug Evaluation, Preclinical; Female; HEK293 Cells; Humans; Lung; Mice, Inbred C57BL; Mutation; Peptide Elongation Factor 1; Peptides, Cyclic; Phosphoproteins; RNA, Viral; SARS-CoV-2; Virus Replication; COVID-19 Drug Treatment; Mice
PubMed: 33495306
DOI: 10.1126/science.abf4058 -
Cancer Treatment Reviews Oct 2014Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on... (Review)
Review
Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on historical regimens for aggressive B-cell lymphomas, have resulted in insufficient patient outcomes. The majority of patients relapse rapidly, and current 5-year overall survival rates are only 10-30%. It is evident that new approaches to treat patients with PTCL are required. In recent years, prospective studies in PTCL have been initiated, mainly in patients with relapsed/refractory disease. In some of these, selected histologic subtypes have been evaluated in detail. As a consequence, numerous new therapies have been developed and shown activity in PTCL, including: agents targeting the immune system (e.g. brentuximab vedotin, alemtuzumab, lenalidomide); histone deacetylase inhibitors (romidepsin, belinostat); antifolates (pralatrexate); fusion proteins (denileukin diftitox); nucleoside analogs (pentostatin, gemcitabine); and other agents (e.g. alisertib, plitidepsin, bendamustine, bortezomib). A variety of interesting novel combinations is also emerging. It is hoped that these innovative approaches, coupled with a greater understanding of the clinicopathologic features, pathogenesis, molecular biology, and natural history of PTCL will advance the field and improve outcomes in this challenging group of diseases. This review summarizes the currently available clinical evidence on the various approaches to treating relapsed/refractory PTCL, including the role of stem cell transplantation, with an emphasis on potential new drug therapies.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Cyclophosphamide; Depsipeptides; Diphtheria Toxin; Doxorubicin; Folic Acid Antagonists; Histone Deacetylase Inhibitors; Humans; Immunoconjugates; Interleukin-2; Lenalidomide; Lymphoma, T-Cell, Peripheral; Neoplasm Recurrence, Local; Peptides, Cyclic; Prednisolone; Recombinant Fusion Proteins; Stem Cell Transplantation; Thalidomide; Topoisomerase Inhibitors; Vincristine
PubMed: 25199959
DOI: 10.1016/j.ctrv.2014.08.001 -
BioRxiv : the Preprint Server For... Feb 2021Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide and massive...
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide and massive societal and economic burden. Recently, a new variant of SARS-CoV-2, known as B.1.1.7, was first detected in the United Kingdom and is spreading in several other countries, heightening public health concern and raising questions as to the resulting effectiveness of vaccines and therapeutic interventions. We and others previously identified host-directed therapies with antiviral efficacy against SARS-CoV-2 infection. Less prone to the development of therapy resistance, host-directed drugs represent promising therapeutic options to combat emerging viral variants as host genes possess a lower propensity to mutate compared to viral genes. Here, in the first study of the full-length B.1.1.7 variant virus , we find two host-directed drugs, plitidepsin (aplidin; inhibits translation elongation factor eEF1A) and ralimetinib (inhibits p38 MAP kinase cascade), as well as remdesivir, to possess similar antiviral activity against both the early-lineage SARS-CoV-2 and the B.1.1.7 variant, evaluated in both human gastrointestinal and lung epithelial cell lines. We find that plitidepsin is over an order of magnitude more potent than remdesivir against both viruses. These results highlight the importance of continued development of host-directed therapeutics to combat current and future coronavirus variant outbreaks.
PubMed: 33501437
DOI: 10.1101/2021.01.24.427991 -
Potential role of marine species-derived bioactive agents in the management of SARS-CoV-2 infection.Future Microbiology Nov 2021COVID-19, caused by the SARS-CoV-2 outbreak, has resulted in a massive global health crisis. Bioactive molecules extracted or synthesized using starting material...
COVID-19, caused by the SARS-CoV-2 outbreak, has resulted in a massive global health crisis. Bioactive molecules extracted or synthesized using starting material obtained from marine species, including griffithsin, plitidepsin and fingolimod are in clinical trials to evaluate their anti-SARS-CoV-2 and anti-HIV efficacies. The current review highlights the anti-SARS-CoV-2 potential of marine-derived phytochemicals explored using , and models. The current literature suggests that these molecules have the potential to bind with various key drug targets of SARS-CoV-2. In addition, many of these agents have anti-inflammatory and immunomodulatory potentials and thus could play a role in the attenuation of COVID-19 complications. Overall, these agents may play a role in the management of COVID-19, but further preclinical and clinical studies are still required to establish their role in the mitigation of the current viral pandemic.
Topics: Alkaloids; Anti-Inflammatory Agents; Antiviral Agents; Depsipeptides; Fingolimod Hydrochloride; Humans; Lectins; Marine Biology; Molecular Docking Simulation; Oceans and Seas; Peptides, Cyclic; Phycocyanin; Phytochemicals; Plant Lectins; Polyphenols; Polysaccharides; SARS-CoV-2; Seaweed; Sesquiterpenes; COVID-19 Drug Treatment
PubMed: 34689597
DOI: 10.2217/fmb-2021-0024 -
Oncotarget Apr 2019Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus,...
Despite recent progress in its treatment, Multiple Myeloma (MM) remains incurable and its associated bone disease persists even after complete remission. Thus, identification of new therapeutic agents that simultaneously suppress MM growth and protect bone is an unmet need. Herein, we examined the effects of Aplidin, a novel anti-cancer marine-derived compound, on MM and bone cells. In vitro, Aplidin potently inhibited MM cell growth and induced apoptosis, effects that were enhanced by dexamethasone (Dex) and bortezomib (Btz). Aplidin modestly reduced osteocyte/osteoblast viability and decreased osteoblast mineralization, effects that were enhanced by Dex and partially prevented by Btz. Further, Aplidin markedly decreased osteoclast precursor numbers and differentiation, and reduced mature osteoclast number and resorption activity. Moreover, Aplidin reduced Dex-induced osteoclast differentiation and further decreased osteoclast number when combined with Btz. Lastly, Aplidin alone, or suboptimal doses of Aplidin combined with Dex or Btz, decreased tumor growth and bone resorption in bone organ cultures that reproduce the 3D-organization and the cellular diversity of the MM/bone marrow niche. These results demonstrate that Aplidin has potent anti-myeloma and anti-resorptive properties, and enhances proteasome inhibitors blockade of MM growth and bone destruction.
PubMed: 31105871
DOI: 10.18632/oncotarget.26831 -
Frontiers in Pharmacology 2021There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical...
There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18 % had an IC below 25 µM or 10 IU/ml. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.
PubMed: 33841165
DOI: 10.3389/fphar.2021.646676 -
Marine Drugs Mar 2024The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell... (Review)
Review
The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as druggable pivotal players orchestrating tumor metastasis and angiogenesis, thus positioning them as prime targets for cancer treatment. A range of HIF inhibitors, notably natural compounds originating from marine organisms, exhibit encouraging anticancer properties, underscoring their significance as promising therapeutic options. Bioprospection of the marine environment is now a well-settled approach to the discovery and development of anticancer agents that might have their medicinal chemistry developed into clinical candidates. However, despite the massive increase in the number of marine natural products classified as 'anticancer leads,' most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy.
Topics: Animals; Humans; Antineoplastic Agents; Aquatic Organisms; Basic Helix-Loop-Helix Transcription Factors; Biological Products; Hypoxia-Inducible Factor 1; Neoplasms; Signal Transduction
PubMed: 38667760
DOI: 10.3390/md22040143 -
EClinicalMedicine Jun 2022The main objective of the present study was to analyze both clinical characteristics and evolution during hospitalization of a cohort of patients admitted for COVID-19...
BACKGROUND
The main objective of the present study was to analyze both clinical characteristics and evolution during hospitalization of a cohort of patients admitted for COVID-19 pneumonia who were not vaccinated, or with a complete or incomplete vaccination schedule.
METHODS
This COVID-19 specialized single-center cohort study of 1888 COVID-19 patients hospitalized at the "Enfermera Isabel Zendal" Emergencies Hospital (HEEIZ), Madrid (Spain) was performed between July 1 and September 30, 2021. It compared the results of 1327 hospitalized unvaccinated patients to 209 hospitalized fully vaccinated and 352 hospitalized partially vaccinated patients. The four different COVID-19 vaccines authorized in Spain during the time-period studied were: BNT162b2 (Pfizer); ChAdOx1 nCoV-19 (AstraZeneca), mRNA-1273 (Moderna); Ad26.COV2.S (Janssen).
FINDINGS
Hospitalized patients' median age was 41 years (IQR 33-50) for the unvaccinated and 61 years (IQR 53-67) for the fully vaccinated ones. The main comorbidities were obesity, hypertension and diabetes mellitus. 20% of unvaccinated patients (266) required noninvasive respiratory care, as did 14% (51) of partially and 14% (30) of fully vaccinated; 6% (78) of the unvaccinated patients also needed invasive respiratory care, as did 5% (16) of partially and 11 (5%) fully vaccinated.
INTERPRETATION
Fully vaccinated patients were 84% (95% CI: 82-86%) less likely to be admitted to hospital, and protection rose for those aged <50 years. Once hospitalized, vaccinated patients displayed more protection against requiring respiratory care than unvaccinated ones, despite being older and having more comorbidities. No differences appeared for the four studied COVID-19 vaccines and complying with vaccination recommendations proved relevant.
FUNDING
The research was funded by the "Plan Propio de Investigación" Program of the Castilla-La Mancha University /European Regional Development Fund (2021-GRIN-31,039).
PubMed: 35611064
DOI: 10.1016/j.eclinm.2022.101453 -
Annals of Hematology Sep 2019The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at... (Randomized Controlled Trial)
Randomized Controlled Trial
The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator's assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Depsipeptides; Dexamethasone; Disease-Free Survival; Female; Humans; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Peptides, Cyclic; Survival Rate; Thalidomide
PubMed: 31240472
DOI: 10.1007/s00277-019-03739-2