Thapsigargin mechanism of action

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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

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. 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. In both cell lines, Tg-induced cell death depended on death receptor 5 and caspase Interestingly, IRE1 contributed to Tg-induced cell death in a cell type-specific manner. Molecular requirements for cell death induction by therapy-relevant Tg analogs were identical to those observed with Tg. Together, our results provide a new, integrated understanding of UPR signaling mechanisms and downstream mediators that induce cell death upon Tg-triggered, unmitigated ER stress.

Chen et al. However, the presence of SERCA pump in almost all kind of cells and its essential role for cell survival, makes Tg a general cell toxin [ 5557 ].

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

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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Apoptosis via DR5 and caspase Cell death induced by endoplasmic reticulum stress. Mahalingam D. After h incubation with Boc-8ADT, the K d values are as low, or lower, than those observed with the other inhibitors Table 1. Table 2 Phase II clinical trials of mipsagargin. Biomed Pharmacother. Toxicol in Vitro. Trends Biochem Sci. Nucleic Acids Res. Brown M.

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.

To alleviate this stress, cells activate a network of signaling pathways known as the unfolded protein response UPR that, depending on the level of damage, restores protein homeostasis adaptive UPR or triggers apoptosis apoptotic UPR [ 28 , 29 , 30 , 31 ]. An initial phase of JNK activation inhibits cell death early in the endoplasmic reticulum stress response. Chidawanyika T. For a , c , d , and f : Dots represent individual values, with a separate color for each experiment. Multiple pictures from each well were taken every 3 h. ER stress-induced cell death may occur through activation of both intrinsic and extrinsic apoptotic pathways, involving Bcl-2 proteins Bim, Noxa, and Puma and tumor necrosis factor-related apoptosis-inducing ligand TRAIL receptors [ 30 ]. Figure S5. To measure cell death, 2. PC3 cells were seeded in standard growth medium and exposed for 24 h to 0. Secondly, a recent report showed that while XBP1 mediated adaptive signals at non-cytotoxic, low levels of ER stress, it could mediate pro-apoptotic effects via upregulating the expression of the transcription factor KLF9 at cytotoxic, high levels of ER stress in WI38 human fibroblasts [ ]. Experiments were initiated 2 days after transfection. Das A. Despite that the O-8—substituted analogs only differ in the structure of the N-terminal residue of the O-8 side chain, they do reveal different properties in their effects on cells. Table 1 Cell death mode and key mediators involved in Tg action in various cancer cell lines.