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Inhibition of EIF2α Dephosphorylation Decreases Cell Viability and Synergizes with Standard-of-Care Chemotherapeutics in Head and Neck Squamous Cell Carcinoma.

Drug resistance is a common cause of therapy failure in head and neck squamous cell carcinoma (HNSCC). One approach to tackling it is by targeting fundamental cellular processes, such as translation. The eukaryotic translation initiation factor 2α (EIF2α) is a key player in canonical translation initiation and integrates diverse stress signals; when phosphorylated, it curbs global protein synthesis. This study evaluates EIF2α expression and phosphorylation in HNSCC. A small-molecule inhibitor of EIF2α dephosphorylation, salubrinal, was tested in vitro, followed by viability assays, flow cytome

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… Mammalian Unfolded Protein Response Inhibits Cyclin D1 Translation and Cell-Cycle Progression. Proc. Natl. Acad. Sci. USA. 1999;96:8505–8510. doi: 10.1073/pnas.96.15.8505. 63. Ding Z., Liu Y., Rubio V., He J., Minze L.J., Shi Z.-Z. …

European Medicines Agency review of ixazomib (Ninlaro) for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

On 21 November 2016, the European Commission issued a marketing authorisation valid throughout the European Union for ixazomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Ixazomib was evaluated in one, randomised, double-blind, phase III study comparing ixazomib plus lenalidomide and dexamethasone (n=360; ixazomib arm) versus placebo plus lenalidomide and dexamethasone (n=362; placebo arm) in adult patients with relapsed and/or refractory multiple myeloma who had received at least one

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… Ixazomib treatment of an MM cell line resulted in caspase-mediated apoptosis, accompanied by induction of the unfolded protein response, increases in several pro-apoptotic BH3-only proteins and an apoptotic cascade. …

Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects.

The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely

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… The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation Science 2011 334 1081 1086 10.1126/science.1209038 22116877 12. Ri M. Endoplasmic-reticulum stress pathway-associated mechanisms of action of proteasome inhibitors in multiple myeloma Int. J. …

Биомаркеры IgG в многоразовом склерозе: расшифровка их связей с протеином Pazzing Protein.

Определение надежных биомаркеров в периферической крови имеет решающее значение для улучшения диагностики и управления множественным склерозом (МС), особенно с учетом инвазивного характера отбора проб цереброспиновой жидкости (CSF). В настоящем обзоре рассматривается роль клеток В и иммуноглобулинов (Igs), в частности IgG и IgM, в качестве биомаркеров для MS. В клеточные олиголональные полосы (OCBs) в CSF являются хорошо зарекомендовавшими себя диагностическими инструментами, однако периферийные биомаркеры по-прежнему недостаточно развиты. Появляющиеся данные свидетельствуют о структурных и фу

Genome agnostic, multi-level non-oncogene addiction-based systems pharmacology for rescuing metastatic relapsed/refractory neoplasias.

Rescue therapies for relapsed/refractory (r/r) metastatic neoplasias present significant unmet needs. Tumor tissue editing regimen for 13 r/r tumor types, carcinomas, sarcomas and hematologic neoplasias, included in 15 phase I/II trials, nuclear/cytokine receptor agonists, pioglitazone, plus/minus dexamethasone or all-trans retinoic acid or interferon-α to counterbalance tumor tissue homeostasis and reprogramming of cancer hallmarks, stress response inhibitors, COX-2 inhibitor, everolimus, lenalidomide, or clarithromycin, and a stress response inducer, low-dose metronomic chemotherapy with tre

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… The unfolded protein response (UPR) is then activated and may be involved in PPAR activities ( He Jiang et al., 2024 ). …

RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and

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… Orchestrating the unfolded protein response in health and disease. J Clin Invest. 2002;110:1389–1398. doi: 10.1172/JCI16886. 26. Araki E, Oyadomari S, Mori M. Endoplasmic reticulum stress and diabetes mellitus. Intern Med. 2003;42:7–14. doi: 10.2169/internalmedicine.42.7. 27. Cvek B, Dvorak Z. …

Biomolecular condensates as dynamic regulators of musculoskeletal homeostasis, disease, and therapeutic challenges.

Biomolecular condensates are membraneless assemblies that concentrate proteins, nucleic acids, and other biomolecules into dynamic cellular compartments. Liquid-liquid phase separation (LLPS) is one important route by which such condensates form, particularly when multivalent interactions generate liquid-like, reversible assemblies. However, not every condensate or disease-associated assembly should be explained solely by LLPS. In the musculoskeletal system, condensates have been linked to transcription, signal transduction, RNA metabolism, stress responses, tissue development, homeostasis, an

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… Under the stressful conditions of hypoxia and low glucose in the bone marrow, disseminated tumor cells activate the unfolded protein response, notably upregulating the 78-kD glucose-regulated protein (GRP78), a UPR chaperone to form SGs, which maintain proteostasis and promote cell survival. 133 These …

Tumor microenvironment signaling and therapeutics in cancer progression.

Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell-to-cell and cell-to-ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss t

A rare case of a minimally secretory plasma cell leukemia with a hemorrhagic gastric plasmacytoma.

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Anti-Angiogenic Activity of Drugs in Multiple Myeloma.

Angiogenesis represents a pivotal hallmark of multiple myeloma (MM) that correlates to patients' prognosis, overall survival, and drug resistance. Hence, several anti-angiogenic drugs that directly target angiogenic cytokines (i.e., monoclonal antibodies, recombinant molecules) or their cognate receptors (i.e., tyrosine kinase inhibitors) have been developed. Additionally, many standard antimyeloma drugs currently used in clinical practice (i.e., immunomodulatory drugs, bisphosphonates, proteasome inhibitors, alkylating agents, glucocorticoids) show anti-angiogenic effects further supporting t

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… Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107:4907–4916. doi: 10.1182/blood-2005-08-3531. 88. Tan C.R.C., Abdul-Majeed S., Cael B., Barta S.K. Clinical Pharmacokinetics and Pharmacodynamics of Bortezomib. Clin. …

Прогресс в лечении множественной миеломы.

Множественная миелома (ММ) является вторым по распространенности гематологической злокачественности в мире. Несмотря на свою репутацию агрессивного и смертельного заболевания, недавние улучшения в лечении значительно улучшили результаты лечения. За последнее десятилетие появились инновационные методы лечения с меньшим числом побочных эффектов, включая протеиновые ингибиторы (например, борцезомиб, карфилзомиб, ixazomib), моноколональные антитела (например, даратумумаб, изатуксимаб, элотузумаб), иммуномуляторы (например, талидомид, линалидомид, помалидомид) и кортикостероиды (например, дексамета

PLP2 Could Be a Prognostic Biomarker and Potential Treatment Target in Glioblastoma Multiforme.

ObjectiveThis study aimed to discern the association between PLP2 expression, its biological significance, and the extent of immune infiltration in human GBM.MethodsUtilizing the GEPIA2 and TCGA databases, we contrasted the expression levels of PLP2 in GBM against normal tissue. We utilized GEPIA2 and LinkedOmics for survival analysis, recognized genes co-expressed with PLP2 via cBioPortal and GEPIA2, and implemented GO and KEGG analyses. The STRING database facilitated the construction of protein-protein interaction networks. We evaluated the relationship of PLP2 with tumor immune infiltrates

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… subunit 15A (PPP1R15A), also known as growth arrest and DNA damage-inducible protein 34 (GADD34), 57 plays a pivotal role in a fundamental biological process within mammalian cells known as the integrated stress response (ISR). 58 This process, which is evolutionarily conserved, can be linked to both the unfolded-protein … Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha . J Cell Biol . 2001 ; 153 ( 5 ): 1011 – 1022 . doi: 10.1083/jcb.153.5.1011 11381086 PMC2174339 69. Malhi H , Kaufman RJ . Endoplasmic reticulum stress in liver disease . …

Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia.

The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia (CML), greatly prolonged the life of CML patients, and improved their prognosis. However, TKI resistance is still a major problem with CML patients, reducing the efficacy of treatment and their quality of life. TKI resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent resistance. Now, the main clinical strategy addressing TKI resistance is to switch to newly developed TKIs. However, data have shown that these new drugs may cause serio

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… Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells Blood 107 12 2006 4907 4916 16507771 10.1182/blood-2005-08-3531 PMC1895817 12 Reff M.J. Shillingburg A. Shah B. Elder C. Prescott H. Kennerly-Shah J. …

Inhibition of autophagy enhances the antitumour activity of tigecycline in multiple myeloma.

Accumulating evidence shows that tigecycline, a first-in-class glycylcycline, has potential antitumour properties. Here, we found that tigecycline dramatically inhibited the proliferation of multiple myeloma (MM) cell lines RPMI-8226, NCI-H929 and U266 in a dose and time-dependent manner. Meanwhile, tigecycline also potently impaired the colony formation of these three cell lines. Mechanism analysis found that tigecycline led to cell cycle arrest at G0/G1 with down-regulation of p21, CDK2 and cyclin D1, rather than induced apoptosis, in MM cells. Importantly, we found that tigecycline induced

Marketed nonsteroidal anti-inflammatory agents, antihypertensives, and human immunodeficiency virus protease inhibitors: as-yet-unused weapons of the oncologists' arsenal.

Experimental data indicate that several pharmacological agents that have long been used for the management of various diseases unrelated to cancer exhibit profound in vitro and in vivo anticancer activity. This is of major clinical importance, since it would possibly aid in reassessing the therapeutic use of currently used agents for which clinicians already have experience. Further, this would obviate the time-consuming process required for the development and the approval of novel antineoplastic drugs. Herein, both pre-clinical and clinical data concerning the antineoplastic function of dist

Mechanism and therapeutic potential of traditional Chinese medicine extracts in sepsis.

Sepsis is a complex syndrome characterized by multi-organ dysfunction, due to the presence of harmful microorganisms in blood which could cause mortality. Complications associated with sepsis involve multiple organ dysfunction. The pathogenesis of sepsis remains intricate, with limited treatment options and high mortality rates. Traditional Chinese medicine (TCM) has consistently demonstrated to have a potential on various disease management. Its complements include reduction of oxidative stress, inhibiting inflammatory pathways, regulating immune responses, and improving microcirculation. Tra

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… During endoplasmic reticulum stress, the unfolded protein response sensor may undergo a unique signal switch to induce cell death. … Multiple mechanisms of unfolded protein response–induced cell death . Am. J. Pathol. 185 , 1800 – 1808 . 10.1016/j.ajpath.2015.03.009 25956028 PMC4484218 Honma K. Udono H. Kohno T. Yamamoto K. Ogawa A. Takemori T. ( 2005 ). …

Research progress on the anti-cancer mechanisms of edible salty-flavored Chinese materia medica.

Edible salty-flavored Chinese materia medica (ESCM) refers to a category of traditional Chinese medicine (TCM) that also serve as food, characterized by their salty flavor. According to the TCM theory, ESCM can soften and disperse knots, thus potentially offering benefits for cancer prevention and treatment. With cancer remaining a major global health challenge, its primary prevention strategies, especially through dietary modification, are crucial. ESCM have recently garnered substantial attention, due to their remarkable clinical efficacy and low side-effect profile. Researches on ESCM demon

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… Various physiological and pathological conditions can lead to an accumulation of misfolded proteins in the ER lumen—a conserved adaptive reaction known as ER stress, and triggering the unfolded protein response (UPR) ( Fu et al., 2021 ; Bhat et al., 2017 ). … Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer. Biochim. Biophys. Acta Rev. Cancer 1867 (1), 58–66. 10.1016/j.bbcan.2016.12.002 Blaser H., Dostert C., Mak T. W., Brenner D. (2016). TNF and ROS crosstalk in inflammation. …

Новые тенденции в нанобиосистемах Змей-Веном-Лоадед: всеобъемлющий обзор.

Достижения в медицинской нанобиотехнологии в значительной степени способствовали применению ядов змеиных токсинов, облегчая разработку новых методов лечения токсинов, производимых животными. Огромное разнообразие видов змей и их ядовые сложности подчеркивают необходимость продолжения исследований. Этот обзор посвящен изучению интеграции яда змеиных ядов с наночастицами, с тем чтобы они могли использоваться в лечении человека в целях разработки методов лечения. Сложная смесь яда змей не только вызывает значительные патологические последствия, но и позволяет получить ценные знания для создания н

Механистические и переводческие данные о натуральных продуктах растительного происхождения в предклинических исследованиях по миеломе: текущие данные.

Множественная миелома (ММ) — гематологическая порча, характеризующаяся клональным распространением аномальных плазменных клеток с ярко выраженной гетерогенностью и терапевтической рефлексорностью. Несмотря на внедрение протеазонных ингибиторов (ИП), иммуноводных препаратов (ИМИД), моноклонных антител (mAbs) и химерика антигенного рецептора Т-клеток (CAR-T), рецидивы и резистентность к лекарствам по-прежнему остаются серьезными проблемами, требующими неотложного решения. В последние годы природные продукты растительного происхождения привлекают все большее внимание в связи с их многоцелевым син

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… Resveratrol also targets the unfolded protein response (UPR), activating inositol-requiring enzyme 1α (IRE1α) to induce X-box binding protein 1 (XBP1) mRNA splicing in ANBL-6, OPM2, and MM.1S cell lines. …

Роль растворимого CD40L в аутоиммунных заболеваниях.

CD40-CD40L имеет важное значение для модуляции иммунной системы, поскольку она координирует как адаптивные, так и подстрекательские реакции. К числу аутоиммунных заболеваний относятся системная волчанка, множественный склероз, воспалительный кишечник, тромбоцитопентическая пурпура и ревматоидный артрит. Таким образом, ось CD40-CD40L является значительной терапевтической целью, несмотря на тот факт, что ее ингибирование было сначала ограничено тромбоэмболическими негативными последствиями. В результате проведенных в последнее время исследований были разработаны новые терапевтические подходы, та