Thapsigargin

Thapsigargin is an inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2⁺ ATPase pump.^[1] Thapsigargin can induce a potent host antiviral response that blocks influenza A virus replication at nano-molar non-cytotoxic levels.^[2]

In vitro efficacy test it shown that HEp2 cells primed with 0.5 µM Thapsigargin (as a non-cytotoxic inhibitor) before infection reduced progeny virus production by almost 10,000-fold. A549 cells primed with 0.3 µM Thapsigargin, in turn, was more inhibitory than the RDV-treated cells by 450-fold.^[3] In vitro, treatment with 10 μM of Thapsigargin (a specific blocker SERCAs), can null EMF response by impairing the replenishment of the ER.^[4] In vitro test it indicated that treatment with 0.001 μM - 1 μM of thapsigargin may arrest cell proliferations in MH7A human rheumatoid arthritis synovial cells in a time- and dose-dependent manner.^[5] Treatment with 1 μM of thapsigargin mediated sensitization to TRAIL in ESCC cell lines through the activation of AMPK from the aspects of protein function and existence.^[7]

In vivo efficacy study it demonstrated that treatment with 0.5ug/g/body weight of Thapsigargin was safe and did not elicit any adverse effects on survival in mice.^[6] In vivo, mice were treated with 1 mg/kg thapsigargin and 60 mg/kg hrTRAIL intraperitoneally for five times per week, improved the expression of CHOP, increased AMPK phosphorylation, increased the expression of DR5, increased the expression of Bax, and activated Caspase 9, while suppressing Bcl2 expression.^[7]

References:
[1].Lytton J., Westlin M., Hanley M.R. Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J. Biol. Chem. 1991;266:17067–17071.
[2].Goulding L.V., Yang J., Jiang Z., Zhang H., Lea D., Emes R.D., Dottorini T., Pu J., Liu J., Chang K.C. Thapsigargin at non-cytotoxic levels induces a potent host antiviral response that blocks influenza A virus replication. Viruses. 2020;12:1093.
[3].Al-Beltagi S, et al. Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus. Viruses. 2021 Feb 3;13(2):234.
[4].Bertagna F, et al. Thapsigargin blocks electromagnetic field-elicited intracellular Ca2⁺ increase in HEK 293 cells. Physiol Rep. 2022 May;10(9):e15189.
[5].Wang H, et al. Effects of thapsigargin on the proliferation and survival of human rheumatoid arthritis synovial cells. ScientificWorldJournal. 2014 Feb 9;2014:605416.
[6].Abdullahi A, et al. Modeling Acute ER Stress in Vivo and in Vitro. Shock. 2017 Apr;47(4):506-513.
[7].Ma Z, et al. Thapsigargin sensitizes human esophageal cancer to TRAIL-induced apoptosis via AMPK activation. Sci Rep. 2016 Oct 12;6:35196.