Thapsigargin mechanism of action

Cell Communication and Signaling volume 18Article number: 12 Cite this article.

Federal government websites often end in. The site is secure. Box Blindern, Oslo, Norway,. However, the exact mechanisms whereby SERCA inhibition induces cell death are incompletely understood. Here, we report that low 0.

Thapsigargin mechanism of action

Federal government websites often end in. The site is secure. A sesquiterpene lactone, thapsigargin, is a phytochemical found in the roots and fruits of Mediterranean plants from Thapsia L. This biological activity encouraged studies on the use of thapsigargin as a novel antineoplastic agent, which were, however, hampered due to high toxicity of this compound to normal cells. In this review, we summarized the recent knowledge on the biological activity and molecular mechanisms of thapsigargin action and advances in the synthesis of less-toxic thapsigargin derivatives that are being developed as novel anticancer drugs. The skin-irritating properties, as well as the medical use of this plant, were known already in ancient times. The resin from the roots and fruits of T. The skin irritating component, named Tg, was isolated from T. The structural complexity of this carbon skeleton was challenging for organic chemists [ 2 ]. The first total synthesis of Tg from S -carvone, achieved in 42 steps with 0. Christensen and co-workers described a concise synthesis of Tg from nortribolide in [ 8 ].

Over the past 40 years, several excellent reviews describing Tg and its derivatives at different angles have been published [ 12121314 ]. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. In contrast, cells with a rounded and compact appearance were scored as affected but still living because they could regain thapsigargin mechanism of action morphology and replicative function after washout of inhibitor data not shown.

Thapsigargin raises cytosolic intracellular calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula. Store-depletion can secondarily activate plasma membrane calcium channels , allowing an influx of calcium into the cytosol. Depletion of ER calcium stores leads to ER stress and activation of the unfolded protein response. Thapsigargin treatment and the resulting ER calcium depletion inhibits autophagy independent of the UPR. Thapsigargin is useful in experimentation examining the impacts of increasing cytosolic calcium concentrations and ER calcium depletion.

Despite the great success of vaccines that protect against RNA virus infections, and the development and clinical use of a limited number of RNA virus-specific drugs, there is still an urgent need for new classes of antiviral drugs against circulating or emerging RNA viruses. To date, it has proved difficult to efficiently suppress RNA virus replication by targeting host cell functions, and there are no approved drugs of this type. This opinion article discusses the recent discovery of a pronounced and sustained antiviral activity of the plant-derived natural compound thapsigargin against enveloped RNA viruses such as severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 , Middle East respiratory syndrome coronavirus MERS-CoV , and influenza A virus. Based on its mechanisms of action, thapsigargin represents a new prototype of compounds with multimodal host-directed antiviral activity. Abstract Despite the great success of vaccines that protect against RNA virus infections, and the development and clinical use of a limited number of RNA virus-specific drugs, there is still an urgent need for new classes of antiviral drugs against circulating or emerging RNA viruses.

Thapsigargin mechanism of action

Cell Communication and Signaling volume 18 , Article number: 12 Cite this article. Metrics details. Cell death triggered by unmitigated endoplasmic reticulum ER stress plays an important role in physiology and disease, but the death-inducing signaling mechanisms are incompletely understood. To gain more insight into these mechanisms, the ER stressor thapsigargin Tg is an instrumental experimental tool. Additionally, Tg forms the basis for analog prodrugs designed for cell killing in targeted cancer therapy. Tg induces apoptosis via the unfolded protein response UPR , but how apoptosis is initiated, and how individual effects of the various UPR components are integrated, is unclear. Furthermore, the role of autophagy and autophagy-related ATG proteins remains elusive.

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J Natl Cancer Inst. Characterization of calcium release-activated apoptosis of LNCaP prostate cancer cells. Cell death is plotted as the ratio of red fluorescence to total cell confluence after 60 A or 72 h B and C normalized to the highest cell death level obtained with Tg. Sci Transl Med. Jeffrey M. Cell Biol. The dotted lines are inserted for visual aid only i. To our knowledge, this is the first time that LC3 has been implicated as a contributor to cell death induced by a classical ER stressor. A study from the University of Nottingham showed promising results for its use against Covid and other coronavirus. Single points represent individual measurements mean values from triplicate wells , and each experiment is indicated with differently colored points. To overcome these limitations, we set out to target each of the main UPR components with two different siRNAs per target in two different cell lines and assess the effects on Tg-induced cell death, caspase activity, and DR5- and LC3B expression. We consider it likely that the long delays and slender fluorescent peaks observed with the above mentioned analogs, at least in part, reflect retarded passage of the analogs across the outer cell membrane as compared with Tg.

Thapsigargin, the first representative of the hexaoxygenated guaianolides, was isolated 40 years ago in order to understand the skin-irritant principles of the resin of the umbelliferous plant Thapsia garganica. Thapsigargin has become a tool for investigation of the importance of SERCA in intracellular calcium homeostasis. In addition, complex formation of thapsigargin with SERCA has enabled crystallization and structure determination of calcium-free states by X-ray crystallography.

ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Although Tg had a promising anti-leukemic activity in mouse models of human T-ALL, its administration was limited due to its high toxicity [ 65 ]. Absolute configurations of the histamine liberating sesquiterpene lactones thapsigargin and trilobolide. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. In conclusion, our data indicate that Tg-induced cell death involves a non-autophagic function of LC3B upstream of procaspase-8 cleavage. Thus, DR4 was neither required for Tg-induced cell death nor could compensate for the lack of DR5 with regard to Tg-induced cell death, in any of the cell lines. In contrast, even if the preincubation period of the other analogs including EpoTg is similarly extended, there is no additional effect on inhibition beyond that taking place after 3—6 min data not shown. Plant Cell Tiss. For all cell lines and inhibitors, there was an increased cell density during the 1st day with continued but reduced proliferation rates before the second phase with definitive and deleterious changes that eventually resulted in cell death taking place in the following days. To enhance our understanding of ER stress-induced cell death initiation, we in the following parts sought to elucidate how the various components of the UPR integrate on the regulation of cell death and the expression of DR5 and LC3B. The low-yield tedious isolation of Tg from T. First, because 0. References 1. Compared to Tg, the analogs show differences in their interaction with SERCA burial of the extended prodrug linker and display a slower binding to SERCA, even though the analogs bind to the same binding site [ 10 , 15 , , ].