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Infectious Diseases (London, England) Jul 2024To study the effect of plitidepsin antiviral treatment in immunocompromised COVID-19 patients with underlying haematological malignancies or solid tumours, particularly... (Observational Study)
Observational Study
Outcomes and clinical characteristics of the compassionate use of plitidepsin in COVID-19 patients with solid tumours, haematological malignancies or anti-CD20 antibody treatment.
OBJECTIVE
To study the effect of plitidepsin antiviral treatment in immunocompromised COVID-19 patients with underlying haematological malignancies or solid tumours, particularly those who have undergone anti-CD20 therapies.
DESIGN
We conducted a retrospective observational study, involving 54 adults treated with plitidepsin on compassionate use as an antiviral drug. Our analysis compared outcomes between patients with solid tumours and those with haematological malignancies, and a cohort of cases treated or not with anti-CD20 monoclonal antibodies.
RESULTS
Patients with a history of anti-CD20 therapies showed a prolonged time-to-negative RT-PCR for SARS-CoV-2 infection compared to non-treated patients (33 d (28;75) vs 15 (11;25); = .002). Similar results were observed in patients with solid tumours in comparison to those with haematological malignancies (13 (10;16) vs 26 (17;50); < .001). No serious adverse events were documented.
CONCLUSIONS
Patients with haematological malignancies appear to be at a heightened risk for delayed SARS-CoV-2 clearance and subsequent clinical complications. These findings support plitidepsin as a well-tolerated treatment in this high-risk group. A phase II clinical trial (NCT05705167) is ongoing to evaluate plitidepsin as an antiviral drug in this population.KEY POINTSHaematological patients face an increased risk for severe COVID-19.Anti-CD20 therapies could increase fatal outcomes in COVID-19 patients.Persistent viral replication is increased in immunocompromised patients.Plitidepsin does not lead to new serious adverse events in immunocompromised patients.
Topics: Humans; Male; Female; Retrospective Studies; Middle Aged; Hematologic Neoplasms; Aged; Depsipeptides; Neoplasms; COVID-19 Drug Treatment; Peptides, Cyclic; SARS-CoV-2; COVID-19; Antiviral Agents; Treatment Outcome; Adult; Compassionate Use Trials; Immunocompromised Host; Antigens, CD20; Aged, 80 and over
PubMed: 38743059
DOI: 10.1080/23744235.2024.2351043 -
Pharmacological Research Jun 2024Eukaryotic elongation factor 1A (eEF1A) is among the most abundant proteins in eukaryotic cells. Evolutionarily conserved across species, eEF1A is in charge of... (Review)
Review
Eukaryotic elongation factor 1A (eEF1A) is among the most abundant proteins in eukaryotic cells. Evolutionarily conserved across species, eEF1A is in charge of translation elongation for protein biosynthesis as well as a plethora of non-translational moonlighting functions for cellular homeostasis. In malignant cells, however, eEF1A becomes a pleiotropic driver of cancer progression via a broad diversity of pathways, which are not limited to hyperactive translational output. In the past decades, mounting studies have demonstrated the causal link between eEF1A and carcinogenesis, gaining deeper insights into its multifaceted mechanisms and corroborating its value as a prognostic marker in various cancers. On the other hand, an increasing number of natural and synthetic compounds were discovered as anticancer eEF1A-targeting inhibitors. Among them, plitidepsin was approved for the treatment of multiple myeloma whereas metarrestin was currently under clinical development. Despite significant achievements in these two interrelated fields, hitherto there lacks a systematic examination of the eEF1A protein in the context of cancer research. Therefore, the present work aims to delineate its clinical implications, molecular oncogenic mechanisms, and targeted therapeutic strategies as reflected in the ever expanding body of literature, so as to deepen mechanistic understanding of eEF1A-involved tumorigenesis and inspire the development of eEF1A-targeted chemotherapeutics and biologics.
Topics: Humans; Peptide Elongation Factor 1; Neoplasms; Animals; Antineoplastic Agents; Molecular Targeted Therapy; Clinical Relevance
PubMed: 38677532
DOI: 10.1016/j.phrs.2024.107195 -
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 -
Journal of Immunology (Baltimore, Md. :... Apr 2024Plitidepsin is a host-targeted compound known for inducing a strong anti-SARS-CoV-2 activity, as well as for having the capacity of reducing lung inflammation. Because...
Plitidepsin is a host-targeted compound known for inducing a strong anti-SARS-CoV-2 activity, as well as for having the capacity of reducing lung inflammation. Because IL-6 is one of the main cytokines involved in acute respiratory distress syndrome, the effect of plitidepsin in IL-6 secretion in different in vitro and in vivo experimental models was studied. A strong plitidepsin-mediated reduction of IL-6 was found in human monocyte-derived macrophages exposed to nonproductive SARS-CoV-2. In resiquimod (a ligand of TLR7/8)-stimulated THP1 human monocytes, plitidepsin-mediated reductions of IL-6 mRNA and IL-6 levels were also noticed. Additionally, although resiquimod-induced binding to DNA of NF-κB family members was unaffected by plitidepsin, a decrease in the regulated transcription by NF-κB (a key transcription factor involved in the inflammatory cascade) was observed. Furthermore, the phosphorylation of p65 that is required for full transcriptional NF-κB activity was significantly reduced by plitidepsin. Moreover, decreases of IL-6 levels and other proinflammatory cytokines were also seen in either SARS-CoV-2 or H1N1 influenza virus-infected mice, which were treated at low enough plitidepsin doses to not induce antiviral effects. In summary, plitidepsin is a promising therapeutic agent for the treatment of viral infections, not only because of its host-targeted antiviral effect, but also for its immunomodulatory effect, both of which were evidenced in vitro and in vivo by the decrease of proinflammatory cytokines.
Topics: Humans; Animals; Mice; NF-kappa B; Influenza A Virus, H1N1 Subtype; Interleukin-6; Antiviral Agents; Immunologic Factors; Cytokines; SARS-CoV-2; Depsipeptides
PubMed: 38416036
DOI: 10.4049/jimmunol.2300426 -
Angewandte Chemie (International Ed. in... Mar 2024Plitidepsin (or dehydrodidemnin B), an approved anticancer drug, belongs to the didemnin family of cyclic depsipeptides, which are found in limited quantities in marine...
Plitidepsin (or dehydrodidemnin B), an approved anticancer drug, belongs to the didemnin family of cyclic depsipeptides, which are found in limited quantities in marine tunicate extracts. Herein, we introduce a new approach that integrates microbial and chemical synthesis to generate plitidepsin and its analogues. We screened a Tistrella strain library to identify a potent didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in a didemnin B titer of approximately 75 mg/L. Next, we developed two straightforward chemical strategies to convert didemnin B into plitidepsin, one of which involved a one-step synthetic route giving over 90 % overall yield. Furthermore, we synthesized 13 new didemnin derivatives and three didemnin probes, enabling research into structure-activity relationships and interactions between didemnin and proteins. Our study highlights the synergistic potential of biosynthesis and chemical synthesis in overcoming the challenge of producing complex natural products sustainably and at scale.
Topics: Peptides, Cyclic; Depsipeptides; Antineoplastic Agents; Structure-Activity Relationship
PubMed: 38291557
DOI: 10.1002/anie.202318784 -
The Journal of Biological Chemistry Mar 2024Eukaryotic elongation factor 1A1 (EEF1A1) is canonically involved in protein synthesis but also has noncanonical functions in diverse cellular processes. Previously, we...
Eukaryotic elongation factor 1A1 (EEF1A1) is canonically involved in protein synthesis but also has noncanonical functions in diverse cellular processes. Previously, we identified EEF1A1 as a mediator of lipotoxicity and demonstrated that chemical inhibition of EEF1A1 activity reduced mouse liver lipid accumulation. These findings suggested a link between EEF1A1 and metabolism. Therefore, we investigated its role in regulating metabolic substrate preference. EEF1A1-deficient Chinese hamster ovary (2E2) cells displayed reduced media lactate accumulation. These effects were also observed with EEF1A1 knockdown in human hepatocyte-like HepG2 cells and in WT Chinese hamster ovary and HepG2 cells treated with selective EEF1A inhibitors, didemnin B, or plitidepsin. Extracellular flux analyses revealed decreased glycolytic ATP production and increased mitochondrial-to-glycolytic ATP production ratio in 2E2 cells, suggesting a more oxidative metabolic phenotype. Correspondingly, fatty acid oxidation was increased in 2E2 cells. Both 2E2 cells and HepG2 cells treated with didemnin B exhibited increased neutral lipid content, which may be required to support elevated oxidative metabolism. RNA-seq revealed a >90-fold downregulation of a rate-limiting glycolytic enzyme, hexokinase 2, which we confirmed through immunoblotting and enzyme activity assays. Pathway enrichment analysis identified downregulations in TNFA signaling via NFKB and MYC targets. Correspondingly, nuclear abundances of RELB and MYC were reduced in 2E2 cells. Thus, EEF1A1 deficiency may perturb glycolysis by limiting NFKB- and MYC-mediated gene expression, leading to decreased hexokinase expression and activity. This is the first evidence of a role for a translation elongation factor, EEF1A1, in regulating metabolic substrate utilization in mammalian cells.
Topics: Animals; Cricetinae; Humans; Adenosine Triphosphate; Cell Line; Cricetulus; Hexokinase; Lipids; Peptide Elongation Factor 1; Glycolysis; Oxidation-Reduction; Cell Movement; Cell Proliferation; Lipid Metabolism
PubMed: 38272231
DOI: 10.1016/j.jbc.2024.105684 -
British Journal of Cancer Feb 2024The eukaryotic elongation factor, EEF1A2, has been identified as an oncogene in various solid tumors. Here, we have identified a novel function of EEF1A2 in angiogenesis.
BACKGROUND
The eukaryotic elongation factor, EEF1A2, has been identified as an oncogene in various solid tumors. Here, we have identified a novel function of EEF1A2 in angiogenesis.
METHODS
Chick chorioallantoic membrane, tubulogenesis, aortic ring, Matrigel plug, and skin wound healing assays established EEF1A2's role in angiogenesis.
RESULT
Higher EEF1A2 levels in breast cancer cells enhanced cell growth, movement, blood vessel function, and tubule formation in HUVECs, as confirmed by ex-ovo and in-vivo tests. The overexpression of EEF1A2 could be counteracted by Plitidepsin. Under normoxic conditions, EEF1A2 triggered HIF1A expression via ERK-Myc and mTOR signaling in TNBC and ER/PR positive cells. Hypoxia induced the expression of EEF1A2, leading to a positive feedback loop between EEF1A2 and HIF1A. Luciferase assay and EMSA confirmed HIF1A binding on the EEF1A2 promoter, which induced its transcription. RT-PCR and polysome profiling validated that EEF1A2 affected VEGF transcription and translation positively. This led to increased VEGF release from breast cancer cells, activating ERK and PI3K-AKT signaling in endothelial cells. Breast cancer tissues with elevated EEF1A2 showed higher microvessel density.
CONCLUSION
EEF1A2 exhibits angiogenic potential in both normoxic and hypoxic conditions, underscoring its dual role in promoting EMT and angiogenesis, rendering it a promising target for cancer therapy.
Topics: Humans; Female; Breast Neoplasms; Feedback; Phosphatidylinositol 3-Kinases; Endothelial Cells; Vascular Endothelial Growth Factor A; Angiogenesis; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Peptide Elongation Factor 1
PubMed: 38012382
DOI: 10.1038/s41416-023-02509-2 -
Cell Oct 2023SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC...
SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics.
Topics: Humans; COVID-19; Immunity, Innate; Pandemics; SARS-CoV-2
PubMed: 37738970
DOI: 10.1016/j.cell.2023.08.026 -
International Journal of Infectious... Oct 2023To evaluate the compassionate use of plitidepsin as an antiviral treatment in hospitalized immunocompromised adult patients with moderate-to-severe COVID-19. (Observational Study)
Observational Study
OBJECTIVES
To evaluate the compassionate use of plitidepsin as an antiviral treatment in hospitalized immunocompromised adult patients with moderate-to-severe COVID-19.
DESIGN
Retrospective observational study of data -collected from January 01, 2021 to April 30, 2022- from 35 immunocompromised adult patients with COVID-19 non-eligible for other available antiviral treatments. Main outcome measures were time to respiratory recovery (SpFi ≥ 315); COVID-19-related 30-day-cumulative mortality after first plitidepsin infusion; and time to undetectable levels of viral RNA.
RESULTS
Thirty-three patients receiving a full course of plitidepsin (2.5 mg [n = 29] or 1.5 mg [n = 4]) were included. Most (69.7%) had a malignant hematologic disease and 27.3% had solid tumors. A total of 111 infusions were administered with lack of relevant safety events. Median time from plitidepsin initiation to SpFi ≥315 was 8 days (95% confidence interval [CI], 7-19). Median time to first negative reverse transcription-polymerase chain reaction for SARS-CoV-2 (cycle threshold >36) was 17 days (95% CI 13-25). Mortality rate was 16.3% (95% CI 3-37.3).
CONCLUSION
These data support plitidepsin as a well-tolerated treatment that might have potential clinical and antiviral efficacy in COVID-19 immunocompromised patients.
Topics: Humans; Adult; COVID-19; SARS-CoV-2; Compassionate Use Trials; Neoplasms; Antiviral Agents
PubMed: 37481109
DOI: 10.1016/j.ijid.2023.07.011 -
Journal of Intensive Care Medicine Nov 2023The occurrence of pneumomediastinum (PM) and/or pneumothorax (PTX) in patients with severe pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)... (Observational Study)
Observational Study
INTRODUCTION
The occurrence of pneumomediastinum (PM) and/or pneumothorax (PTX) in patients with severe pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was evaluated.
METHODS
This was a prospective observational study conducted in patients admitted to the intermediate respiratory care unit (IRCU) of a COVID-19 monographic hospital in Madrid (Spain) between December 14, 2020 and September 28, 2021. All patients had a diagnosis of severe SARS-CoV-2 pneumonia and required noninvasive respiratory support (NIRS): high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and bilevel positive airway pressure (BiPAP). The incidences of PM and/or PTX, overall and by NIRS, and their impact on the probabilities of invasive mechanical ventilation (IMV) and death were studied.
RESULTS
A total of 1306 patients were included. 4.3% (56/1306) developed PM/PTX, 3.8% (50/1306) PM, 1.6% (21/1306) PTX, and 1.1% (15/1306) PM + PTX. 16.1% (9/56) of patients with PM/PTX had HFNC alone, while 83.9% (47/56) had HFNC + CPAP/BiPAP. In comparison, 41.7% (521/1250) of patients without PM and PTX had HFNC alone (odds ratio [OR] 0.27; 95% confidence interval [95% CI] 0.13-0.55; < .001), while 58.3% (729/1250) had HFNC + CPAP/BiPAP (OR 3.73; 95% CI 1.81-7.68; < .001). The probability of needing IMV among patients with PM/PTX was 67.9% (36/53) (OR 7.46; 95% CI 4.12-13.50; < .001), while it was 22.1% (262/1185) among patients without PM and PTX. Mortality among patients with PM/PTX was 33.9% (19/56) (OR 4.39; 95% CI 2.45-7.85; < .001), while it was 10.5% (131/1250) among patients without PM and PTX.
CONCLUSIONS
In patients admitted to the IRCU for severe SARS-CoV-2 pneumonia requiring NIRS, incidences of PM/PTX, PM, PTX, and PM + PTX were observed to be 4.3%, 3.8%, 1.6%, and 1.1%, respectively. Most patients with PM/PTX had HFNC + CPAP/BiPAP as the NIRS device, much more frequently than patients without PM and PTX. The probabilities of IMV and death among patients with PM/PTX were 64.3% and 33.9%, respectively, higher than those observed in patients without PM and PTX, which were 21.0% and 10.5%, respectively.
Topics: Humans; SARS-CoV-2; COVID-19; Respiratory Care Units; Mediastinal Emphysema; Pneumothorax; Pneumonia; Oxygen Inhalation Therapy; Respiratory Insufficiency; Noninvasive Ventilation
PubMed: 37306158
DOI: 10.1177/08850666231180165