期刊
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
卷 49, 期 1, 页码 18-26出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejps.2013.02.003
关键词
Shikonin; Ewing sarcoma; Cytotoxic chemotherapy; Natural product; Transcription; High throughput screen
To search for compounds that disrupt binding of the EWS-FLII fusion protein to its cognate targets, we developed a homogeneous high-throughput proximity assay and screened 5200 small molecule compounds. Many well-known DNA-binding chemotherapeutic agents, such as actinomycin D, cisplatin, doxorubicin, daunorubicin, and epirubicin scored in the assay and not surprising also disrupted the binding of other transcription factors. Unexpectedly, we found that Shikonin, a natural product from the root of Lithospermum erythrorhizon, similarly disrupted protein-DNA interactions. Mechanistic studies demonstrated that Shikonin displaces SYBR green from binding to the minor groove of DNA and is able to inhibit topoisomerase mediated DNA relaxation. In cells, Shikonin blocked the binding of EWS-FLI1 to the NR0B1 promoter, and attenuated gene expression. Shikonin rapidly induced G2/M arrest and apoptosis in Ewing sarcoma cells. These results demonstrate that contrary to other purported mechanisms of action, Shikonin is a DNA-binding cytotoxic agent. (C) 2013 Elsevier B.V. All rights reserved.
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