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The Host Cell ViroCheckpoint: Identification and Pharmacologic Targeting of Novel Mechanistic Determinants of Coronavirus-Mediated Hijacked Cell States

Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell proteins that are critically dysregulated following virus-mediated reprogramming of the host cell transcriptional state. To overcome these limitations, we propose that elucidation and pharmacologic targeting of host cell Master Regulator proteins—whose aberrant activities govern the reprogramed state of infected-coronavirus cells—presents unique opportunities to develop novel mechanism-based therapeutic approaches to antiviral therapy, either as monotherapy or as a complement to establ

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… The HSP90 inhibitors SNX-2112 and luminespib, as well as the sarco/endoplasmatic reticulum Ca 2+ ATPase inhibitor thapsigargin, all identified by ViroTreat as inverters of the SARS- CoV induced checkpoint, have been shown to inhibit herpes simplex( 74 ), chikungunya( 75 ), foot and mouth disease virus …

Effects of the polyunsaturated fatty acids, EPA and DHA, on hematological malignancies: a systematic review.

Omega-3 polyunsaturated fatty acids (PUFAs) have well established anti-cancer properties. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are among this biologically active family of macromolecules for which various anti-cancer effects have been explained. These PUFAs have a high safety profile and can induce apoptosis and inhibit growth of cancer cells both in vitro and in vivo, following a partially selective manner. They also increase the efficacy of chemotherapeutic agents by increasing the sensitivity of different cell lines to specific anti-neoplastic drugs. Various mechanisms

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… R Benedetti A Bygrave FL On the mechanism of action of econazole, the capacitative calcium inflow blocker Biochemical and biophysical research communications 1998 248 75 7 9675088 10.1006/bbrc.1998.8810 50 Jan CR Ho CM Wu SN Tseng CJ Multiple effects of econazole on calcium signaling: depletion of thapsigargin-sensitive …

CHAC1: a master regulator of oxidative stress and ferroptosis in human diseases and cancers.

CHAC1, an essential regulator of oxidative stress and ferroptosis, is increasingly recognized for its significant roles in these cellular processes and its impact on various human diseases and cancers. This review aims to provide a comprehensive overview of CHAC1's molecular functions, regulatory mechanisms, and effects in different pathological contexts. Specifically, the study objectives are to elucidate the biochemical pathways involving CHAC1, explore its regulatory network, and discuss its implications in disease progression and potential therapeutic strategies. As a γ-glutamyl cyclotrans

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… ChaC1 mRNA expression is upregulated in response to ER stress-inducing agents such as thapsigargin, tunicamycin, and brefeldin A. The transcriptional regulation of ChaC1 involves two critical elements in its promoter: the ATF4 and the amino acid response element (AARE). … Using luciferase reporter assays and DNA binding studies, they demonstrated that ATF4 directly binds to these elements, enhancing CHAC1 expression under ER stress conditions induced by chemicals like Thapsigargin and Tunicamycin. …

Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1.

The Golgi apparatus is increasingly recognized as a major hub for cellular signaling and is involved in numerous pathologies, including neurodegenerative diseases and cancer. The study of Golgi stress-induced signaling pathways relies on the selectivity of the available tool compounds of which currently only a few are known. To discover novel Golgi-fragmenting agents, transcriptomic profiles of cells treated with brefeldin A, golgicide A, or monensin were generated and compared with a database of gene expression profiles from cells treated with other bioactive small molecules. In parallel, a p

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… Compounds were obtained from the following companies: brefeldin A (Sigma-Aldrich), golgicide A (Santa Cruz Biotechnology), monensin (Enzo Life Sciences), AG-1478 (Sigma), tunicamycin (Santa Cruz Biotechnology), thapsigargin (Santa Cruz Biotechnology), nocodazole (Santa Cruz Biotechnology), (+)-JQ1 (Cayman …

Development of an Active Chimeric IL13Rα2 ADC for Diffuse Intrinsic Pontine Glioma.

IntroductionDiffuse intrinsic pontine glioma (DIPG) is a rare pediatric brain tumor with a critical unmet need due to the lack of approved, curative interventions available. The interweaving of malignant cells with normal tissue makes surgical extraction essentially impossible, and radiation provides only transient benefit. The recent ONC201 FDA approval, however, suggests DIPG therapy is tractable. Having identified overexpression of IL13Rα2 in DIPG tumor tissue versus normal brain tissue, we investigated binding of commercially available IL13Rα2 monoclonal antibodies. The top candidate antib

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… Excluding some resistant DIPG cell lines (DIPG-6 and DIPG-24), the 6-day half maximal inhibitory concentrations (IC 50 ) of exatecan (the chemotherapy from which deruxtecan, Supplementary Figure 3 , is derived), thapsigargin, MMAE, DM1, PBD monomer and PBD dimer against DIPG were all less than 10 nM …

Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.

Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function. This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones, folding enzymes, and degradation machineries. Disruptions in this network lead to dysproteostasis, a pathological state implicated in a growing list of human diseases, including neurodegenerative disorders, metabolic syndromes, and cancer. In this review, we provide a comp

Targeting Cancer Through Thymoquinone: From Molecular Mechanisms to Clinical Prospects.

Thymoquinone (TQ), the active compound in Nigella sativa (black seed), has shown promising effects against cancer in many laboratory studies. In this review, we explore how TQ works on different aspects of cancer, from stopping cancer cell growth and spread, to triggering cancer cell death, reducing inflammation, and helping the immune system fight back. We also highlight how TQ may overcome one of the biggest problems in cancer treatment-chemoresistance. When used together with common treatments like chemotherapy, radiation, or immunotherapy, TQ has been shown to improve their effects and red

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… Currently, there is no direct evidence in the scientific literature demonstrating that TQ synergizes with classical ER stress inducers such as tunicamycin or thapsigargin in cancer models. …

Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment.

Growing evidence shows that nerves play an active role in cancer development and progression by altering crucial molecular pathways and cell functions. Conversely, the use of neurotropic drugs, such as tricyclic antidepressants (TCAs), may modulate these molecular signals with a therapeutic purpose based on a direct antitumoral effect and beyond the TCA use to treat neuropathic pain in oncology patients. In this review, we discuss the TCAs' safety and their central effects against neuropathic pain in cancer, and the antitumoral effects of TCAs in in vitro and preclinical studies, as well as in

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… Differential impact of imipramine on thapsigargin- and tunicamycin-induced endoplasmic reticulum stress and mitochondrial dysfunction in neuroblastoma SH-SY5Y cells. Eur. J. Pharmacol. 2021;902:174073. doi: 10.1016/j.ejphar.2021.174073. 66. …

T-Type Calcium Channels: A Mixed Blessing.

The role of T-type calcium channels is well established in excitable cells, where they preside over action potential generation, automaticity, and firing. They also contribute to intracellular calcium signaling, cell cycle progression, and cell fate; and, in this sense, they emerge as key regulators also in non-excitable cells. In particular, their expression may be considered a prognostic factor in cancer. Almost all cancer cells express T-type calcium channels to the point that it has been considered a pharmacological target; but, as the drugs used to reduce their expression are not complete

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… . | [ 25 ] Thapsigargin (+/−Nickel) | Prostate cancer | LNCaP cell line | N.A. | [ 125 ] TTA-P2 | Glioma | GIC, GliNS1, G179NS, and G166NS, U3NNN-MG cell lines | N.A. | [ 125 ] TTA-P2 | Glioma | Xenograft injection | Not reported | [ 125 ] In terms of cancer therapy, Ca 2+ channel blockers are administered …

Exosomal circRNAs: Deciphering the novel drug resistance roles in cancer therapy.

Exosomal circular RNA (circRNAs) are pivotal in cancer biology, and tumor pathophysiology. These stable, non-coding RNAs encapsulated in exosomes participated in cancer progression, tumor growth, metastasis, drug sensitivity and the tumor microenvironment (TME). Their presence in bodily fluids positions them as potential non-invasive biomarkers, revealing the molecular dynamics of cancers. Research in exosomal circRNAs is reshaping our understanding of neoplastic intercellular communication. Exploiting the natural properties of exosomes for targeted drug delivery and disrupting circRNA-mediate

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… Thapsigargin sensitizes human esophageal cancer to TRAIL-induced apoptosis via AMPK activation. Sci. Rep. 2016;6 doi: 10.1038/srep35196. 7. Guo W., Qiao T., Li T. The role of stem cells in small-cell lung cancer: Evidence from chemoresistance to immunotherapy. Semin. …

Immune Dysfunction in Uremia 2020.

Cardiovascular disease and infections are major causes for the high incidence of morbidity and mortality of patients with chronic kidney disease. Both complications are directly or indirectly associated with disturbed functions or altered apoptotic rates of polymorphonuclear leukocytes, monocytes, lymphocytes, and dendritic cells. Normal responses of immune cells can be reduced, leading to infectious diseases or pre-activated/primed, giving rise to inflammation and subsequently to cardiovascular disease. This review summarizes the impact of kidney dysfunction on the immune system. Renal failur

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… Thapsigargin-induced calcium entry and apoptotic death of neutrophils are blocked by activation of protein kinase C Pharmacology 2001 63 191 196 10.1159/000056132 11598426 34. Hu T.H. Bei L. Huang Y.F. Shen X. …

Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer.

Prostate cancer (PCa) is the second-most common cancer in men worldwide and treatment options for patients with advanced or aggressive prostate cancer or recurrent disease continue to be of limited success and are rarely curative. Despite immune checkpoint blockade (ICB) efficacy in some melanoma, lung, kidney and breast cancers, immunotherapy efforts have been remarkably unsuccessful in PCa. One hypothesis behind this lack of efficacy is the generation of a distinctly immunosuppressive prostate tumor microenvironment (TME) by regulatory T cells, MDSCs, and type 2 macrophages which have been i

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… Notably, addition of exogenous ER stress-inducers thapsigargin or dithiothreitol effectively converts neutrophils into LOX-1+ PMN-MDSCs [ 92 ]. …

Oleocanthal as a Multifunctional Anti-Cancer Agent: Mechanistic Insights, Advanced Delivery Strategies, and Synergies for Precision Oncology.

Oleocanthal (OC), a secoiridoid phenolic compound exclusive to extra virgin olive oil (EVOO), has emerged as a promising nutraceutical with multifaceted anti-cancer properties. Despite its well-characterized anti-inflammatory and antioxidant effects, the mechanistic breadth and translational potential of OC in oncology remain underexplored and fragmented across the literature. This comprehensive review synthesizes and critically analyzes recent advances in the molecular, pharmacological, and translational landscape of OC's anti-cancer activities, providing an integrative framework to bridge pr

Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies.

Metastatic dissemination of solid tumors, a leading cause of cancer-related mortality, underscores the urgent need for enhanced insights into the molecular and cellular mechanisms underlying metastasis, chemoresistance, and the mechanistic backgrounds of individuals whose cancers are prone to migration. The most prevalent signaling cascade governed by multi-kinase inhibitors is the mitogen-activated protein kinase (MAPK) pathway, encompassing the RAS-RAF-MAPK kinase (MEK)-extracellular signal-related kinase (ERK) pathway. RAF kinase is a primary mediator of the MAPK pathway, responsible for th

Прогресс в развитии лекарственных средств на основе пептида: платформы для доставки, терапевтические средства и вакцины.

Успешное утверждение лекарств на основе пептида можно отнести на счет совместных усилий по целому ряду дисциплин. Интеграция новых методов разработки и синтеза лекарственных средств, отображение библиотечных технологий, систем доставки, достижений в области биоинженерии и искусственного интеллекта в значительной степени ускорила разработку новейших лекарств на основе пептида, эффективно устраняя препятствия, связанные с их характером, такие, как быстрое обезвреживание и деградация, необходимость субколичественной инъекции, ведущей к усилению дискомфорта пациентов, и в конечном итоге продвигая

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… Phase I 5 BT8009 118 (Bicycle Therapeutics) Nectin-4- binder MMAE Amide Solid tumors NCT04180371 Phase I/II 6 TH1902 793 TH19P01 Docetaxel Succinic acid Solid tumors NCT04561362 Phase I 7 TH1904 794 TH19P01 Doxorubicin Succinic acid Solid tumors NCT04706962 Phase I 8 G-202 795 (mipsagargin) DγEγEγEγE Thapsigargin … ) | Nectin-4- binder | MMAE | Amide | Solid tumors | NCT04180371 Phase I/II 6 | TH1902 793 | TH19P01 | Docetaxel | Succinic acid | Solid tumors | NCT04561362 Phase I 7 | TH1904 794 | TH19P01 | Doxorubicin | Succinic acid | Solid tumors | NCT04706962 Phase I 8 | G-202 795 (mipsagargin) | DγEγEγEγE | Thapsigargin …

UEG Week 2017 Oral Presentations

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Invited Lectures : Overviews Purinergic signalling: past, present and future.

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Abstracts of the 5(th) Cachexia Conference, Barcelona, Spain, December 5-8, 2009.

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Endoplasmic reticulum stress in disease pathogenesis: its implications for therapy.

Endoplasmic reticulum (ER) stress is a key cellular mechanism that is important in the development of many diseases, including cancer. Since the discovery of the unfolded protein response (UPR), research has greatly improved our understanding of how ER stress affects cellular functions, especially protein folding and adaptation to stress. The UPR consists of three main branches: IRE1, ATF6, and PERK, each of which is crucial for regulating stress responses, protein homeostasis, and apoptosis. These pathways normally help cells handle stress effectively; however, excessive or prolonged activati

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… 2007, Jiang et al. first used the ER stress inducer tunicamycin for the treatment of melanoma, which can sensitize melanoma cells to apoptosis by activating IRE1 and ATF6 and thus upregulating TRAIL-R2. 237 When melanoma cells are subjected to pharmacological ER stress induced by tunicamycin (TM) or thapsigargin …

Colorectal Cancer at the Crossroads: The Good, the Bad, and the Future of Platinum-Based Drugs.

Colorectal cancer (CRC) remains a significant global health challenge, ranking third in incidence and second in mortality among cancers worldwide. This review addresses the complex landscape of CRC, focusing on incidence, mortality trends, preventive strategies, and the evolving therapeutic approaches, particularly highlighting the role of platinum-based drugs like oxaliplatin (OXP). It also underscores the increasing burden of CRC, with factors such as westernized diets, aging populations, and genetic predispositions contributing to its prevalence. Therapeutically, early detection greatly enh

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… . − CDP only induces extracellular release of HMGB1 protein, which is similar to OXP , but it does not cause ICD unless combined with ER stress inducers such as thapsigargin. …