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Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer

文献类型：期刊论文

作者Li, Xiaoguang2,3; Zhou, Yu4; Liu, Yanling3; Zhang, Xu4; Chen, Tao3; Chen, Kerong4; Ba, Qian2,3; Li, Jingquan2,3; Liu, Hong4; Wang, Hui1,2,3
刊名EBIOMEDICINE
出版日期2016-12
卷号14页码:44-54
关键词Dihydroartemisinin Drug conjugates Cell cycle Apoptosis Metastasis Ovarian cancer
ISSN号2352-3964
DOI10.1016/j.ebiom.2016.11.026
文献子类Article
英文摘要Artemisinin (ARS) and its derivatives, which are clinically used antimalarial agents, have shown antitumor activities. Their therapeutic potencies, however, are limited by their low solubility and poor bioavailability. Here, through a pharmacophore hybridization strategy, we synthesized ARS-drug conjugates, in which the marketed chemotherapeutic agents chlorambucil, melphalan, flutamide, aminoglutethimide, and doxifluridine, were separately bonded to Dihydroartemisinin (DHA) through various linkages. Of these, the artemisinin-melphalan conjugate, ARS4, exhibited most toxicity to human ovarian cancer cells but had low cytotoxicity to normal cells. ARS4 inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis, and inhibition of migration; these effects were stronger than those of its parent drugs, DHA and melphalan. Furthermore, ARS4 modulated the expression of proteins involved in cell cycle progression, apoptosis, and the epithelialmesenchymal transition (EMT). Moreover, in mice, ARS4 inhibited growth and intraperitoneal dissemination and metastasis of ovarian cancer cells without observable toxic effects. Our results provide a basis for development of the compound as a chemotherapeutic agent. Research in context: Artemisinin compounds have recently received attention as anticancer agents because of their clinical safety profiles and broad efficacy. However, their therapeutic potencies are limited by low solubility and poor bioavailability. Here, we report that ARS4, an artemisinin-melphalan conjugate, possesses marked invitro and in-vivo antitumor activity against ovarian cancer, the effects of which are stronger than those for its parent drugs, Dihydroartemisinin and melphalan. In mice, ARS4 inhibits localized growth of ovarian cancer cells and intraperitoneal dissemination and metastasis without appreciable host toxicity. Thus, for patients with ovarian cancer, ARS4 is a promising chemotherapeutic agent.(C) 2016 The Authors. Published by Elsevier B.V.
WOS关键词EPITHELIAL-MESENCHYMAL TRANSITIONS ; BREAST-CANCER ; BIOLOGICAL EVALUATION ; ANTICANCER AGENTS ; DRUG-RESISTANCE ; IN-VITRO ; CELLS ; DERIVATIVES ; PATHWAYS ; METASTASIS
资助项目National Nature Science Foundation[81630086] ; National Nature Science Foundation[91529305] ; National Nature Science Foundation[81302809] ; National Nature Science Foundation[81672763] ; National Nature Science Foundation[81502122] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020319] ; Science and Technology Commission of Shanghai Municipality[14391901800] ; Food Safety Research Center[00000000] ; Key Laboratory of Food Safety of INS, SIBS, CAS[00000000]
WOS研究方向General & Internal Medicine ; Research & Experimental Medicine
语种英语
WOS记录号WOS:000395256000011
出版者ELSEVIER SCIENCE BV
源URL[http://119.78.100.183/handle/2S10ELR8/275771]  
专题药物化学研究室
通讯作者Liu, Hong; Wang, Hui
作者单位1.Minist Hlth, Key Lab Food Safety Risk Assessment, Beijing, Peoples R China
2.Shanghai Jiao Tong Univ, Sch Med, Sch Publ Hlth, 227 South Chongqing Rd, Shanghai 200025, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Key Lab Food Safety Res, Shanghai 200031, Peoples R China;
4.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai, Peoples R China;
推荐引用方式
GB/T 7714		 Li, Xiaoguang,Zhou, Yu,Liu, Yanling,et al. Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer[J]. EBIOMEDICINE,2016,14:44-54.
APA Li, Xiaoguang.,Zhou, Yu.,Liu, Yanling.,Zhang, Xu.,Chen, Tao.,...&Wang, Hui.(2016).Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer.EBIOMEDICINE,14,44-54.
MLA Li, Xiaoguang,et al."Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer".EBIOMEDICINE 14(2016):44-54.

入库方式： OAI收割

来源：上海药物研究所

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