SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase 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 IC(50) value of 7.75 microM. 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.
State key laboratory of drug research, Division of Anti-tumor pharmacology, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, People's Republic Of China.
Fan
F
Yang
Yi
Y
Chen
Wenhu
W
Duan
Chao
C
Zhang
Hong
H
Zhu
Jian
J
Ding
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004587:Electrophoresis, Agar Gel; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008113:Liver Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009285:Naphthoquinones / Q000378:metabolism* / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D012509:Sarcoma / Q000188:drug therapy; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous
C512540:1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enylfuran-2-caroxylate; D000970:Antineoplastic Agents; D009285:Naphthoquinones; D059005:Topoisomerase II Inhibitors; C016101:shikonin