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
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
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DOI：
10.1158/0008-5472.can-05-4529
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发表时间：
2006-05-01
期刊：
影响因子：
11.2
通讯作者：
Dou, Q. Ping
中科院分区：
文献类型：
--
作者：
Yang, Huanjie;Chen, Di;Dou, Q. Ping
对使用传统药物预防和治疗癌症的兴趣正在增加。体外、体内和临床研究表明蛋白酶体抑制剂作为新型抗癌药物的潜在用途。雷公藤红素是从中药雷公藤的根皮中提取的一种活性化合物，多年来一直被用作治疗炎症的天然药物。虽然雷公藤红素已被证明可诱导白血病细胞凋亡，但涉及的分子靶点尚未确定。此外，雷公藤红素在体内是否具有抗肿瘤活性从未得到最终证实。在此，我们首次报道雷公藤红素有效且优先抑制纯化的20 S蛋白酶体（IC 50 = 2.5 μ mol/L）和人前列腺癌细胞26 S蛋白酶体（1-5 μ mol/L）的胰凝乳蛋白酶样活性。南蛇藤酚在PC-3（雄激素受体或AR阴性）或LNCaP（AR阳性）细胞中抑制蛋白酶体活性，导致泛素化蛋白和三种天然蛋白酶体底物（I κ B-α、Bax和p27）蓄积，同时抑制AR蛋白表达（在LNCaP细胞中）和诱导细胞凋亡。用雷公藤红素（1-3 mg/kg/d，i. p.，1-31天）对肿瘤生长产生显着抑制（65-93%）。使用来自早期和结束时间点的动物肿瘤组织样品的多个测定显示在雷公藤红素处理后蛋白酶体活性的体内抑制和细胞凋亡的诱导。我们的研究结果表明，南蛇藤酚是一种天然的蛋白酶体抑制剂，在癌症预防和治疗方面具有很大的潜力。
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 mu mol/L) and human Prostate cancer cellular 26S proteasome (at 1-5 mu mol/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 (I kappa B-alpha, 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.