Yang H, Zhou P and Huang H contributed equally to this work.
Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo
Article first published online: 3 DEC 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 124, Issue 10, pages 2450–2459, 15 May 2009
How to Cite
Yang, H., Zhou, P., Huang, H., Chen, D., Ma, N., Cui, Q. C., Shen, S., Dong, W., Zhang, X., Lian, W., Wang, X., Dou, Q. P. and Liu, J. (2009), Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo. Int. J. Cancer, 124: 2450–2459. doi: 10.1002/ijc.24195
- Issue published online: 16 MAR 2009
- Article first published online: 3 DEC 2008
- Accepted manuscript online: 3 DEC 2008 12:00AM EST
- Manuscript Accepted: 19 NOV 2008
- Manuscript Received: 7 AUG 2008
- The National High Technology Research and Development Program of China. Grant Number: 2006AA02Z4B5
- National Natural Science Foundation of China. Grant Number: 30770835
- State Education Ministry (Scientific Research Foundation)
- Department of Defense Breast Cancer Research Program. Grant Numbers: W81XWH-04-1-0688, DAMD17-03-1-0175
- National Cancer Institute. Grant Number: 1R01CA120009
- National Cancer Institute/NIH Cancer Center
- medicinal compounds;
- proteasome inhibitor;
- prostate cancer
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 this 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 antitumor property. © 2008 Wiley-Liss, Inc.