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SH‐7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor
Author(s) -
Yang Fan,
Chen Yi,
Duan Wenhu,
Zhang Chao,
Zhu Hong,
Ding Jian
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.21943
Subject(s) - topoisomerase , cytotoxicity , apoptosis , cell culture , in vivo , in vitro , microbiology and biotechnology , cancer research , biology , stereochemistry , chemistry , pharmacology , medicine , biochemistry , genetics
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 IC 50 value of 7.75 μM. One important finding is SH‐7 displayed significant cytotoxicity in the 3 MDR cell lines, with an average IC 50 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.