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.

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. Another way of specifically targeting cancer cells with antineoplastic compounds is via formation of prodrugs activatable by prostate-specific membrane antigen PSMA.

Thus, the degree of abolishment of Tg-induced upregulation of phospho-JNK levels correlated with the degree of downregulation of XBP1s expression levels.

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. A study from the University of Nottingham showed promising results for its use against Covid and other coronavirus. The complete biosynthesis of thapsigargin has yet to be elucidated.

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

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. Development of protocols for selective transformation of thapsigargin disclosed the chemistry and facilitated total synthesis of the molecule. Conversion of trilobolide into thapsigargin offered an economically feasible sustainable source of thapsigargin, which enables a future drug production.

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Methods To systematically address these key questions, we analyzed the effects of Tg and therapeutically relevant Tg analogs in two human cancer cell lines of different origin LNCaP prostate- and HCT colon cancer cells , using RNAi and inhibitory drugs to target death receptors, UPR components and ATG proteins, in combination with measurements of cell death by fluorescence imaging and propidium iodide staining, as well as real-time RT-PCR and western blotting to monitor caspase activity, expression of ATG proteins, UPR components, and downstream ER stress signaling. Yamaguchi H. However, a pro-survival role for ATF6 has been observed in response to chronic, mild ER stress [ 55 ], and knockdown of ATF6 was reported to sensitize melanoma cells to apoptosis induction by Tm or Tg [ 56 ]. Tg-induced cell death partially requires LC3B. Thus, it appears that 0. Andrew Evans. PubChem CID. This inhibition is not irreversible as it is often stated to be for Tg, but it requires dissociation of the inhibitors from the firmly bound E2 complexes of SERCA, e. J Biol Chem. FEBS Lett. Statistics and calculation of RNAi-mediated effects on cell death and protein expression Data are reported as mean of at least 3 independent experiments with SEM as error bars, unless otherwise indicated. Single symbols represent individual measurements for each cell line each symbol represents the mean value from triplicate wells , and each experiment is indicated by differently shaped symbols. A recent study found that glucose deprivation which induces many forms of cellular stress, including ER stress could increase DR4 protein levels without increasing DR4 mRNA levels in HeLa cells, and glucose deprivation-induced cell death showed comparable dependencies on DR4 and DR5 [ 77 ]. The complete biosynthesis of thapsigargin has yet to be elucidated.

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

However, given that ligand-independent death receptor complexes may differ in their requirement for adaptor proteins see further discussion below , our data cannot formally exclude a potential TRADD-independent pro-death involvement of DR1, DR3 or DR6 members in Tg-induced cell death. However, this was not examined in the above-mentioned study. Michelangeli F. Network organization of the human autophagy system. As a library, NLM provides access to scientific literature. The following TaqMan probes Appl. SR vesicles 0. Chua B. Sci Transl Med. S1B and Fig. Ethics declarations Ethics approval and consent to participate Not applicable. DR5 has been shown to play a prominent role in ER stress-induced cell death [ 9 , 13 , 18 , 21 ], but other studies have indicated the involvement of DR4 [ 19 ], TNFR1 [ 26 ], or Fas [ 27 ].