Thapsigargin

Thapsigargin is an inhibitor of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA; IC₅₀ = ~30 nM for the rat liver microsomal enzyme), an ER stress inducer, and a sesquiterpene lactone that has been found in Thapsia.^1,2,3 It increases intracellular calcium levels in isolated rat hepatocytes (EC₅₀ = ~80 nM) and protein levels of the ER stress markers DNA damage-inducible transcript 3 (DDIT3), also known as CHOP, and glucose-regulated protein 78 kDa (GRP78), as well as phosphorylation of protein kinase R-like ER kinase (PERK) and eukaryotic translation initiation factor 2α subunit (eIF2α) in SH-SY5Y cells when used at a concentration of 1 µM. Acute exposure of thapsigargin (2 µg/ml for 1 h) to primary mouse bone marrow-derived macrophages (BMDMs) protects against TNF- and zVAD-induced necroptosis and prolonged exposure of thapsigargin (2-16 µM for 48 h) induces apoptosis in SW-13 adrenocortical carcinoma cells.^4,3 Thapsigargin (3 µM) induces autophagosome accumulation in mouse embryonic fibroblasts (MEFs).⁵ It reduces viral titers in Vero E6 cells co-infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A strain H1N1 when used at a concentration of 0.5 µM.⁶ Thapsigargin (1 mg/kg) reduces tumor volume in an SW-13 mouse xenograft model.³

WARNING This product is not for human or veterinary use.

1. Thastrup, O., Cullen, P.J., Drøbak, B.K., et al. Thapsigargin, a tumor promoter, discharges intracellular Ca²⁺ stores by specific inhibition of the endoplasmic reticulum Ca²⁺-ATPase. Proc. Natl. Acad. Sci. USA 87(7), 2466-2470 (1990).

2. Chen, G., Ma, C., Bower, K.A., et al. Ethanol promotes endoplasmic reticulum stress-induced neuronal death: Involvement of oxidative stress. J. Neurosci. Res. 86, 937-946 (2008).

3. Wu, L., Huang, X., Kuang, Y., et al. Thapsigargin induces apoptosis in adrenocortical carcinoma by activating endoplasmic reticulum stress and the JNK signaling pathway: An in vitro and in vivo study. Drug Des. Devel. Ther. 13, 2787-2798 (2019).

4. Place, D.E., Samir, P., Malireddi, R.K.S., et al. Integrated stress response restricts macrophage necroptosis. Life Sci. Alliance 5(1), e202101260 (2021).

5. Ganley, I.G., Wong, P.-M., Gammoh, N., et al. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol. Cell 42(6), 731-743 (2011).

6. Al-Beltagi, S., Preda, C.A., Goulding, L.V., et al. Thapsigargin is a broad-spectrum inhibitor of major human respiratory ciruses: Coronavirus, respiratory syncytial virus and influenza A virus. Viruses 13(2), 234 (2021).

Fujii, T., Nagamori, S., Wiriyasermkul, P., et al. Parkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H⁺,K⁺-ATPase. Nat. Commun. 14(1), 2174 (2023).

Place, D.E., Samir, P., Malireddi, R.K.S., et al. Integrated stress response restricts macrophage necroptosis. Life Sci. Alliance 5(1), e202101260 (2021).

Nagakannan, P., Islam, M.I., Conrad, M., et al. Cathepsin B is an excutioner of ferroptosis. Biochim. Biophys. Acta Mol. Cell Res. 1868(3), 118928 (2021).

Merhi, A., Delrée, P., and Marini, A. The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling. Sci. Rep. 7, 44602 (2017).

Wang, A., Huen, S.C., Luan, H.H., et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166(6), 1512-1525 (2016).