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.