Celastrol is a proteasome inhibitor with a potent and preferred inhibition of purified 20S proteasome with an IC50 of 2.5 μM. Celastrol is also an antioxidant, anti-inflammatory agent, and immunosuppressant that can be used in the study of cancer, autoimmune diseases, asthma, chronic inflammation, and neurodegenerative diseases [1-2].
1-5 μM Celastrol inhibits the chymotrypsin-like activity of the 26S proteasome in human prostate cancer cells, and in PC-3 and LNCaP (androgen receptor-positive) cells, Celastrol leads to the accumulation of ubiquitinating proteins and proteasome substrates (IKB-A, Bax, and p27). And induce apoptosis [1]. Celastrol (0-1 μM) inhibited the proliferation and migration of AGS and YCC-2 cells and increased the number of cells in G1 phase [3]. In addition, Celastrol (0-10 μM) completely inhibits NF-κB activation in TNF-induced lung adenocarcinoma (H1299) cells and embryonic kidney (A293) cells, and Celastrol does not directly affect NF-κB binding to DNA, but inhibits NF-κB activation by inhibiting IKK activation [4].
In PC-3 tumor-bearing nude mice, Celastrol at 1 or 3 mg/kg significantly inhibited tumor growth, with inhibition rates of 65% and 82%, respectively, and a decrease in chymotrypsin-like activity was detected in the tumors of Celastrol-treated mice. (45% and 30% of the control group respectively) [1]. In a mouse model of gastric cancer xenotransplantation, Celastrol (1 or 2 mg/kg) reduced gastric tumor load in a dose-dependent manner, and Celastrol increased phosphorylated AMPK and decreased phosphorylated AKT and mTOR in gastric tumors [3].
References:
[1] Yang H, Chen D, Cui QC, et al. Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res, 2006, 66(9): 4758-4765.
[2] Salminen A, Lehtonen M, Paimela T, et al. Celastrol: molecular targets of thunder god vine[J]. Biochemical and biophysical research communications, 2010, 394(3): 439-442.
[3] Lee HW, Jang KS, Choi HJ, Jo A, Cheong JH, Chun KH. Celastrol inhibits gastric cancer growth by induction of apoptosis and autophagy. BMB Rep. 2014 Dec;47(12):697-702.
[4] Sethi G, Ahn K S, Pandey M K, et al. Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-κB–regulated gene products and TAK1-mediated NF-κB activation[J]. Blood, 2007, 109(7): 2727-2735.
Celastrol是一种蛋白酶体抑制剂，有效且优先的抑制纯化的20S蛋白酶体，IC50 为2.5 μM。Celastrol也是抗氧化剂、抗炎剂和免疫抑制剂，可用于癌症、自身免疫性疾病、哮喘、慢性炎症和神经退行性疾病的研究[1-2]。
1-5 μM的Celastrol可抑制人前列腺癌细胞26S蛋白酶体的糜蛋白酶样活性，并且在PC-3和LNCaP（雄激素受体阳性）细胞中，Celastrol导致泛素化蛋白和蛋白酶体底物（IKB-A、Bax和p27）的积累，并诱导细胞凋亡[1]。Celastrol（0-1 μM）抑制了AGS和YCC-2细胞的增殖、迁移并增加了G1期的细胞[3]。此外，Celastrol（0-10 μM）完全抑制TNF诱导的肺腺癌（H1299）细胞和胚胎肾（A293）细胞中的NF-κB活化，并且Celastrol不直接影响NF-κB与DNA的结合，而是通过抑制IKK激活来抑制NF-κB的激活[4]。
在PC-3荷瘤裸鼠中，1或3 mg/kg的Celastrol可显著抑制肿瘤生长，抑制率分别为65%和82%，并且Celastrol治疗的小鼠肿瘤中检测到糜蛋白酶样活性降低（分别为对照组的45%和30%）[1]。在胃癌异种移植小鼠模型中，Celastrol（1或2 mg/kg）以剂量依赖性方式减少胃肿瘤负荷，并且Celastrol增加了胃肿瘤中磷酸化的AMPK，减少了磷酸化的AKT和mTOR[3]。