Lu Li, Kanwar Jyoti, Schmitt Sara, Cui Qiuzhi Cindy, Zhang Chuanyin, Zhao Cong, Dou Q Ping
Department of Pathophysiology, Guangzhou Medical University, Guangzhou, Guangdong 510082, China.
Anticancer Res. 2011 Jan;31(1):1-10.
The molecular mechanisms of triptolide responsible for its antitumor properties are not yet fully understood. The ubiquitin/proteasome system is an important pathway of protein degradation in cells. This study investigated whether triptolide may inhibit proteasomal activity and induce apoptosis in human cancer cells.
In vitro proteasome inhibition was measured by incubation of a purified 20S proteasome with triptolide. Human breast and prostate cancer cell lines were also treated with different doses of triptolide for different times, followed by measurement of proteasome inhibition (levels of the chymotrypsin-like activity, ubiquitinated proteins and three well-known proteasome target proteins, p27, IκB-α and Bax) and apoptosis induction (caspase-3 activity and PARP cleavage).
Triptolide did not inhibit the chymotrypsin-like activity of purified 20S proteasome. However, treatment of triptolide was able to cause decreased levels of cellular proteasomal chymotrypsin-like activity and accumulation of ubiquitinated proteins and three well-known proteasome target proteins in human breast and prostate cancer cells, associated with apoptosis induction.
It is possible that at least one of metabolites of triptolide has proteasome-inhibitory activity.
雷公藤甲素抗肿瘤特性的分子机制尚未完全明确。泛素/蛋白酶体系统是细胞内蛋白质降解的一条重要途径。本研究调查了雷公藤甲素是否可能抑制蛋白酶体活性并诱导人癌细胞凋亡。
通过将纯化的20S蛋白酶体与雷公藤甲素一起孵育来测定体外蛋白酶体抑制作用。还用不同剂量的雷公藤甲素对人乳腺癌和前列腺癌细胞系进行不同时间的处理，随后测定蛋白酶体抑制作用（胰凝乳蛋白酶样活性水平、泛素化蛋白以及三种著名的蛋白酶体靶蛋白p27、IκB-α和Bax的水平）和凋亡诱导情况（半胱天冬酶-3活性和聚（ADP-核糖）聚合酶裂解）。
雷公藤甲素未抑制纯化的20S蛋白酶体的胰凝乳蛋白酶样活性。然而，雷公藤甲素处理能够导致人乳腺癌和前列腺癌细胞中细胞蛋白酶体胰凝乳蛋白酶样活性水平降低、泛素化蛋白以及三种著名的蛋白酶体靶蛋白积累，并伴有凋亡诱导。
雷公藤甲素的至少一种代谢产物有可能具有蛋白酶体抑制活性。
