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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 -
Biochemical Pharmacology Feb 2020Plitidepsin (PLD, Aplidin®), a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans, has been recently approved by Australian regulatory...
Plitidepsin (PLD, Aplidin®), a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans, has been recently approved by Australian regulatory authorities for the treatment of multiple myeloma patients. Plitidepsin binds to eEF1A2 and induces oxidative stress, Rac1 activation and JNK1 phosphorylation, triggering a rapid apoptotic program in tumor cells. Since oxidative stress is one of the known sources of endoplasmic reticulum stress, we investigated whether PLD was inducing a bona fide ER stress in HeLa cells and whether this process was essential in the mechanism of action of the compound. Indeed, PLD activated an ER stress-induced unfolded protein response (UPR), including the alternative splicing of XBP1, the proteolytic processing of ATF6 and the phosphorylation of eIF2α and JNK. Interestingly, though PLD induced a strong phosphorylation of eIF2α in all the analyzed cell lines, it did not elicit an increased expression of ATF4 and CHOP, a transcription factor involved in launching UPR-mediated apoptosis. On the contrary, a clear reduction of CHOP protein levels was observed after PLD treatment, most probably due to both the lack of transactivation by ATF4 and its rapid degradation by the ubiquitin/proteasome machinery. Using fibroblasts devoid of each one of the four possible kinases involved in eIF2α phosphorylation, we observed that only PKR was involved in the response to PLD treatment and, accordingly, PKR fibroblasts are shown to be resistant to the apoptogenic activity of the compound. Furthermore, eIF2α phosphorylation itself was shown to be irrelevant for the induction of cell death by PLD. Instead, we reveal that PLD induces an increase in the levels of misfolded proteins while simultaneously inhibiting the autophagic flux. These two effects combined prevent PLD-treated cells from reducing proteotoxic stress and lead to apoptosis. Other anti-myeloma drugs like bortezomib, which target the proteasome, also inhibit the degradation of misfolded proteins through alternate pathways and a synergistic anticancer effect of the PLD plus bortezomib combination has been previously disclosed. The present results extend this synergy to in vivo experiments and provide a mechanistic rationale for this synergy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Depsipeptides; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, SCID; Multiple Myeloma; Neoplasms, Experimental; Oxidative Stress; Peptides, Cyclic; Phosphorylation; Protein Serine-Threonine Kinases; Reactive Oxygen Species; Transcription Factor CHOP
PubMed: 31812675
DOI: 10.1016/j.bcp.2019.113744 -
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 -
The Oncologist Jun 2023T-cell receptor (TCR-T) therapies are based on the expression of an introduced TCR targeting a tumor associated antigen (TAA) which has been studied in several trials in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
T-cell receptor (TCR-T) therapies are based on the expression of an introduced TCR targeting a tumor associated antigen (TAA) which has been studied in several trials in cutaneous melanoma. We conducted a systematic review and meta-analysis aiming to assess the primary efficacy of TCR-based adoptive cell therapy in cutaneous melanoma.
METHODS
We searched through PubMed electronic database from its inception until May 21, 2022. Primary endpoints were pooled objective response rate (ORR) and disease control rate (DCR). We conducted logistic regression analyses to identify potential predictive factors for tumor response.
RESULTS
From 187 patients, 50 showed an objective response (pooled ORR 28%; 95% CI, 20%-37%) and a pooled DCR of 38% (95% CI, 27%-50%). Median PFS was 2, 9 months (95% CI, 1.4-3.1). A trend toward higher PFS was demonstrated for patients treated with cancer/testis antigens targeting TCR-T cells (HR 0.91 95% CI, 0.64-1.3, P = .61) among whom, patients treated with NYESO-1 targeting TCR-T showed a significantly higher PFS (HR 0.63 95% CI, 0.64-0.98, P = .03). In addition, the number of infused cells was associated with a significantly higher likelihood of tumor response (OR 6.61; 95% CI, 1.68-21.6; P = .007).
CONCLUSION
TCR-T therapy shows promising results in terms of antitumor activity and survival similar to those reported for TILs with a significantly higher benefit for cancer/testis antigens targeting cells. Since TCR-based therapy shows advantages of great potential over classic ACT strategies, further research in solid cancers is warranted (PROSPERO ID CRD42022328011).
Topics: Male; Humans; Melanoma; Skin Neoplasms; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Melanoma, Cutaneous Malignant
PubMed: 37036865
DOI: 10.1093/oncolo/oyad078 -
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 -
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 -
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 -
International Journal of Molecular... Mar 2023Eukaryotic elongation factor 1A (eEF1A) canonically delivers amino acyl tRNA to the ribosomal A site during the elongation stage of protein biosynthesis. Yet... (Review)
Review
Eukaryotic elongation factor 1A (eEF1A) canonically delivers amino acyl tRNA to the ribosomal A site during the elongation stage of protein biosynthesis. Yet paradoxically, the oncogenic nature of this instrumental protein has long been recognized. Consistently, eEF1A has proven to be targeted by a wide assortment of small molecules with excellent anticancer activity, among which plitidepsin has been granted approval for the treatment of multiple myeloma. Meanwhile, metarrestin is currently under clinical development for metastatic cancers. Bearing these exciting advances in mind, it would be desirable to present a systematic up-to-date account of the title topic, which, to the best of our knowledge, has thus far been unavailable in the literature. The present review summarizes recent advances in eEF1A-targeting anticancer agents, both naturally occurring and synthetically crafted, with regard to their discovery or design, target identification, structure-activity relationship, and mode of action. Their structural diversity and differential eEF1A-targeting mechanisms warrant continuing research in pursuit of curing eEF1A-driven malignancy.
Topics: Peptide Elongation Factor 1; Protein Biosynthesis; Saccharomyces cerevisiae; Ribosomes; Antineoplastic Agents
PubMed: 36982256
DOI: 10.3390/ijms24065184 -
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 -
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