The first 2 authors contributed equally to this work.
SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor
Article first published online: 28 MAR 2006
Copyright © 2006 Wiley-Liss, Inc.
International Journal of Cancer
Volume 119, Issue 5, pages 1184–1193, 1 September 2006
How to Cite
Yang, F., Chen, Y., Duan, W., Zhang, C., Zhu, H. and Ding, J. (2006), SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor. Int. J. Cancer, 119: 1184–1193. doi: 10.1002/ijc.21943
- Issue published online: 5 JUN 2006
- Article first published online: 28 MAR 2006
- Manuscript Accepted: 31 JAN 2006
- Manuscript Received: 11 OCT 2005
- National Natural Science Foundation. Grant Number: 30228032
- topoisomerase II inhibitor;
1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enylfuran-2-caroxylate (SH-7), a new naphthoquinone compound, derived from shikonin, exhibited obvious inhibitory actions on topoisomerase II (Topo II) and topoisomerase I (Topo I), which were stronger than its mother compound shikonin. Notably, the SH-7's inhibitory potency on Topo II was much stronger than that on Topo I. In addition, SH-7 significantly stabilized Topo II-DNA cleavable complex and elevated the expression of phosphorylated-H2AX. The in vitro cell-based investigation demonstrated that SH-7 displayed wide cytotoxicity in diversified cancer cell lines with the mean IC50 value of 7.75 μM. One important finding is SH-7 displayed significant cytotoxicity in the 3 MDR cell lines, with an average IC50 value nearly equivalent to that of the corresponding parental cell lines. The average resistance factor (RF) of SH-7 was 1.74, which was much lower than those of reference drugs VP-16 (RF 145.92), ADR (RF 105.97) and VCR (RF 197.39). Further studies illustrated that SH-7 had the marked apoptosis-inducing function on leukemia HL-60 cells, which was validated to be of mitochondria-dependence. The in vivo experiments showed that SH-7 had inhibitory effects on S-180 sarcoma implanted to mice, SMMC-7721, BEL-7402 human hepatocellular carcinoma and PC-3 human prostate cancer implanted to nude mice. Taken together, these results suggest that SH-7 induces DSBs as a Topo II inhibitor, which was crucial to activate the apoptotic process, and subsequently accounts for its both in vitro and in vivo antitumor activities. The well-defined Topo II inhibitory activity, antitumor effects particularly with its obvious anti-MDR action, better solubility and less toxicity make SH-7 as a potential antitumor drug candidate for further research and development. © 2006 Wiley-Liss, Inc.