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.

他普西加林是一种肌浆网/内质网Ca2+ ATP酶泵的抑制剂。他普西加林可以在纳摩尔非细胞毒性水平下诱导强效宿主抗病毒反应，阻止流感A病毒的复制。

实验室内的有效性测试表明，在感染前使用0.5微米的硫酸沙脂（作为非细胞毒性抑制剂）预处理HEp2细胞可以将后代病毒产量减少近10,000倍。相反，使用0.3微米硫酸沙脂预处理A549细胞比RDV治疗的细胞更具抑制作用，可使后代病毒产量降低450倍。在体外实验中，使用10微米的硫酸沙脂（一种特定的SERCAs阻断剂），可以通过影响内质网再生来消除EMF响应。体外测试表明，以时间和剂量依赖方式处理MH7A人类类风湿关节炎滑液细胞时，使用0.001-1微米硫酸沙脂可能会阻止其增殖。在ESCc细胞系中，以1微米硫酸沙脂处理介导了对TRAIL敏化作用，并通过AMPK激活从蛋白功能和存在方面进行了验证。

在体内疗效研究中，使用0.5ug/g/体重的Thapsigargin治疗是安全的，并且不会对小鼠的生存产生任何不良影响。在活体实验中，小鼠每周接受1mg/kg Thapsigargin和60mg/kg hrTRAIL腹腔注射五次，在表达CHOP、增加AMPK磷酸化、增加DR5表达、增加Bax表达和激活Caspase 9的同时，抑制了Bcl2的表达。