Thapsigargin mechanism of action

Cell Communication and Signaling volume 18Article 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.

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.

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.

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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.

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.

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. Principles for prodrug development were used by conjugating a payload derived from thapsigargin with a hydrophilic peptide selectively cleaved by proteases in the tumor. Mipsagargin was developed in order to obtain a drug for treatment of cancer diseases characterized by the presence of prostate specific membrane antigen PSMA in the neovascular tissue of the tumors.

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Szalai, and C. Most of the commonly used chemotherapeutics, such as paclitaxel, doxorubicin, or 5-fuorouracil, kill only rapidly-proliferating cells and, as a consequence, are ineffective against cancers that have a low rate of proliferation prostate cancer. In A and C , activities were measured by sequential additions of Tg and Tg analogs in a titration type of experiment under conditions where a substantial fraction of the added inhibitors is bound to the ATPase due to their high affinity to SERCA Lee A. The conjugation of Tg with substrates for such enzymes masks cytotoxic activity of Tg, producing prodrugs that can be cleaved by a tissue-specific proteases expressed only in cancer cells [ 55 , 56 , 57 , 58 ]. Supplementary Material Supplemental Data: Click here to view. Cancer 14 , — [ PubMed ] [ Google Scholar ]. Szalai P, Engedal N. Thapsigargin treatment and the resulting ER calcium depletion inhibits autophagy independent of the UPR. Hence, inducing cell death via ER stress and UPR might be a promising therapeutic strategy for killing cancer cells [ 38 ]. David W. Through the inhibition of SERCA pump, Tg induces cancer cell apoptosis in a proliferation-independent manner [ 55 , 57 ].

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To our knowledge, no single study has so far performed a side-by-side comparison of the relative roles played by the various death receptors in ER stress-induced cytotoxicity. Engedal N. Lytton J. This entails substituting the butanoate at O-8 in Tg Fig. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. Colorectal carcinoma HCT Cas9. SERCA control of cell death and survival. Thapsigargin Fig. This study was supported by the grant from National Science Centre, Poland no. Lee A. With 6 min of preincubation, the concentration-response relationship follows a sigmoid curve with little effect on enzyme activity up to concentrations that otherwise result in almost complete inhibition with the other Tg analogs. Interestingly, IRE1 contributed to Tg-induced cell death in a cell type-specific manner.