雷公藤醇
雷公藤
LNCaP公司
蛋白酶体抑制剂
细胞凋亡
蛋白酶体
体内
药理学
化学
癌症研究
雷公藤甲素
雷公藤
癌细胞
癌症
生物
医学
生物化学
内科学
替代医学
生物技术
病理
有机化学
糖苷
作者
Huanjie Yang,Di Chen,Qiuzhi Cindy Cui,Xiao Yuan,Q. Ping Dou
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2006-05-01
卷期号:66 (9): 4758-4765
被引量:546
标识
DOI:10.1158/0008-5472.can-05-4529
摘要
Abstract Interest in the use of traditional medicines for cancer prevention and treatment is increasing. In vitro, in vivo, and clinical studies suggest the potential use of proteasome inhibitors as novel anticancer drugs. Celastrol, an active compound extracted from the root bark of the Chinese medicine “Thunder of God Vine” (Tripterygium wilfordii Hook F.), was used for years as a natural remedy for inflammatory conditions. Although Celastrol has been shown to induce leukemia cell apoptosis, the molecular target involved has not been identified. Furthermore, whether Celastrol has antitumor activity in vivo has never been conclusively shown. Here, we report, for the first time, that Celastrol potently and preferentially inhibits the chymotrypsin-like activity of a purified 20S proteasome (IC50 = 2.5 μmol/L) and human prostate cancer cellular 26S proteasome (at 1-5 μmol/L). Inhibition of the proteasome activity by Celastrol in PC-3 (androgen receptor- or AR-negative) or LNCaP (AR-positive) cells results in the accumulation of ubiquitinated proteins and three natural proteasome substrates (IκB-α, Bax, and p27), accompanied by suppression of AR protein expression (in LNCaP cells) and induction of apoptosis. Treatment of PC-3 tumor–bearing nude mice with Celastrol (1-3 mg/kg/d, i.p., 1-31 days) resulted in significant inhibition (65-93%) of the tumor growth. Multiple assays using the animal tumor tissue samples from both early and end time points showed in vivo inhibition of the proteasomal activity and induction of apoptosis after Celastrol treatment. Our results show that Celastrol is a natural proteasome inhibitor that has a great potential for cancer prevention and treatment. (Cancer Res 2006; 66(9): 4758-65)
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