SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor

doi:10.1002/ijc.21943

	SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor
	Yang, Fan ; Chen, Yi; Duan, Wenhu; Zhang, Chao ; Zhu, Hong ; Ding, Jian
刊名	INTERNATIONAL JOURNAL OF CANCER
	2006-09-01
卷号	119 期号:5 页码:1184-1193
关键词	SH-7 shikonin topoisomerase II inhibitor antitumor mitochondria
ISSN号	0020-7136
DOI	10.1002/ijc.21943
文献子类	Article
英文摘要	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-Ts 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 mu M. 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. (c) 2006 Wiley-Liss, Inc.
WOS关键词	DOUBLE-STRAND BREAKS ; MULTIDRUG-RESISTANCE ; INDUCED APOPTOSIS ; LITHOSPERMUM-ERYTHRORHIZON ; DNA TOPOISOMERASES ; CELL-DEATH ; IN-VIVO ; CYTOTOXICITY ; EXPRESSION ; INGREDIENT
WOS研究方向	Oncology
语种	英语
出版者	WILEY-LISS
WOS记录号	WOS:000239287800028
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273506]
专题	药物化学研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药理学第一研究室
通讯作者	Duan, Wenhu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Anti Tumor Pharmacol, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Grad Sch, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Yang, Fan,Chen, Yi,Duan, Wenhu,et al. SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor[J]. INTERNATIONAL JOURNAL OF CANCER,2006,119(5):1184-1193.
APA	Yang, Fan,Chen, Yi,Duan, Wenhu,Zhang, Chao,Zhu, Hong,&Ding, Jian.(2006).SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor.INTERNATIONAL JOURNAL OF CANCER,119(5),1184-1193.
MLA	Yang, Fan,et al."SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor".INTERNATIONAL JOURNAL OF CANCER 119.5(2006):1184-1193.