Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo.
Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo.
复制标题
DOI：
10.1002/ijc.24195
复制
发表时间：
2009-05-15
影响因子：
6.4
通讯作者：
Liu, Jinbao
中科院分区：
文献类型：
--
作者：
Yang, Huanjie;Zhou, Ping;Huang, Hongbiao;Chen, Di;Ma, Ningfang;Cui, Qiuzhi Cindy;Shen, Shouxing;Dong, Weihua;Zhang, Xiaoyan;Lian, Wen;Wang, Xuejun;Dou, Q. Ping;Liu, Jinbao
遍在蛋白-蛋白酶体途径的失调在肿瘤生长和发展中发挥着重要作用。紫草素是从中药紫草中分离出来的一种天然萘醌，据报道具有杀伤肿瘤细胞的活性，使用含有紫草素的混合物进行的临床研究结果表明，它对治疗晚期肺癌是安全有效的。本文报道了紫草素在体内外对肿瘤蛋白酶体活性的抑制作用。我们的计算模型预测紫草素的羰基碳C1和C4可能与蛋白酶体的β5胰凝乳蛋白酶亚基的催化位点相互作用。紫草素对纯化的20 S蛋白酶体和肿瘤细胞26 S蛋白酶体的胰凝乳蛋白酶样活性有明显的抑制作用（IC_（50）为12.5 μmol/L），对肿瘤细胞26 S蛋白酶体的IC_（50）为2-16 μmol/L。紫草素抑制小鼠肝癌H22、白血病P388和人前列腺癌PC-3培养物中的蛋白酶体导致泛素化蛋白和几种蛋白酶体靶向促凋亡蛋白（IκB-α、Bax和p27）的积累，随后诱导细胞死亡。紫草素治疗导致H22同种异体移植物和PC-3异种移植物中肿瘤生长抑制，与体内蛋白酶体活性的抑制和细胞死亡的诱导相关。最后，紫草素治疗显著延长了P388白血病小鼠的生存期。结果表明，肿瘤蛋白酶体是紫草素的细胞靶点之一，紫草素抑制肿瘤蛋白酶体活性有助于其抗肿瘤作用。
Dysregulation of the ubiquitin-proteasome pathway plays an essential role in tumor growth and development. Shikonin, a natural naphthoquinone isolated from the traditional Chinese medicine Zi Cao (gromwell), has been reported to possess tumor cell-killing activity, and results from a clinical study using a shikonin-containing mixture demonstrated its safety and efficacy for the treatment of late-stage lung cancer. In the present study, we reported that shikonin is an inhibitor of tumor proteasome activity in vitro and in vivo. Our computational modeling predicts that the carbonyl carbons C1 and C4 of shikonin potentially interact with the catalytic site of β5 chymotryptic subunit of the proteasome. Indeed, shikonin potently inhibits the chymotrypsin-like activity of purified 20S proteasome (IC50 12.5 μmol/L) and tumor cellular 26S proteasome (IC50 between 2-16 μmol/L). Inhibition of the proteasome by shikonin in murine hepatoma H22, leukemia P388 and human prostate cancer PC-3 cultures resulted in accumulation of ubiquitinated proteins and several proteasome target proapoptotic proteins (IκB-α, Bax and p27), followed by induction of cell death. Shikonin treatment resulted in tumor growth inhibition in both H22 allografts and PC-3 xenografts, associated with suppression of the proteasomal activity and induction of cell death in vivo. Finally, shikonin treatment significantly prolonged the survival period of mice bearing P388 leukemia. Our results indicate that the tumor proteasome is one of the cellular targets of shikonin, and inhibition of the proteasome activity by shikonin contributes to its anti-tumor property.
登录
查看更多内容
影响因子：
3.6
作者：
Chiu, Shao-Chih;Yang, Ning-Sun
通讯作者：
Yang, Ning-Sun
影响因子：
5.8
作者：
Kazi, A;Daniel, KG;Dou, QP
通讯作者：
Dou, QP
影响因子：
3.1
作者：
Chen, Di;Chen, Marina S.;Dou, Q. Ping
通讯作者：
Dou, Q. Ping
影响因子：
4.8
作者：
Nam, S;Smith, DM;Dou, QP
通讯作者：
Dou, QP
影响因子：
2.7
作者：
Chen, CH;Chern, CL;Liu, TZ
通讯作者：
Liu, TZ