Thapsigargin mechanism of action

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

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.

Thapsigargin mechanism of action

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. Furthermore, caspase activation and cell death were associated with a sustained unfolded protein response. Experimentally, specific effects of blocking SERCA activity can be conveniently studied with the aid of thapsigargin Tg , a sesquiterpene lactone, the structure of which is shown in Fig. Interestingly, chemically modified analogs of Tg 12 are being used for antineoplastic purposes despite the general cellular toxicity of these compounds against both cancer and normal cells. The problem of toxicity in a therapeutic setting has been addressed by producing inactive prodrugs that can be activated by proteases to target specific cancer types 12 , With respect to prostate cancer, strategies have been designed to produce prodrugs that are transformed into active antineoplastic analogs upon proteolytic cleavage by prostate-specific antigen PSA 14 , This entails substituting the butanoate at O-8 in Tg Fig. In vivo administration of this prodrug leads to extracellular formation of the lipophilic and cytotoxic Tg analog Leu-8ADT Fig.

Chem Biol Drug Des. Oakes S. However, this view has been challenged by reports that indicate a suppressive role of calcineurin and calpains on caspase activation and cell death 35—

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. Substances Antiviral Agents Thapsigargin.

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.

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Primeau J. Figure S8. Abstract Background 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. Together, these results indicate that autophagy and autophagosomal membranes are not required for Tg-induced cell death. Schroder M. Lam M. Interestingly, we found that after pretreatment with 0. 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. One representative blot out of at least 3 independent experiments. In line with this finding, two previous studies have shown that high levels of XBP1s can mediate pro-apoptotic signals.

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.

Data are reported as mean of at least 3 independent experiments with SEM as error bars, unless otherwise indicated. In conclusion, although other death receptors may also play a contributing role, our results and those of others [ 9 , 13 , 17 , 18 , 20 , 21 ] strongly suggest that DR5 is a main hub for ER stress-mediated initiation of cell death across a range of different cell types. Brown M. Interestingly, however, we frequently observed concentrations of Tg and Tg analogs at which the increase in cell density was halted but without concomitant induction of cell death supplemental Fig. Autophagy and autophagy-related ATG proteins are frequently implicated in cell death regulation [ 28 ], but their role in ER stress-induced cell death is unclear. GAPDH and tubulin were used as loading controls. Consent for publication Not applicable. Thapsigargin treatment and the resulting ER calcium depletion inhibits autophagy independent of the UPR. 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. Table 1 Cell death mode and key mediators involved in Tg action in various cancer cell lines. Lastly, we examined the mechanisms of cell death induction by active components of therapeutically relevant Tg prodrugs. Correspondence to Nikolai Engedal.