Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer.
Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer.
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青蒿素化疗药物结合物治疗卵巢癌的临床前疗效和安全性评估
DOI：
10.1016/j.ebiom.2016.11.026
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发表时间：
2016-12
期刊：
影响因子：
11.1
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Li, Xiaoguang;Zhou, Yu;Liu, Yanling;Zhang, Xu;Chen, Tao;Chen, Kerong;Ba, Qian;Li, Jingquan;Liu, Hong;Wang, Hui
青蒿素（Artemisinin，ARS）及其衍生物是临床上常用的抗疟药，具有抗肿瘤活性。然而，它们的治疗效力受限于它们的低溶解度和差的生物利用度。在这里，通过药效团杂交策略，我们合成了ARS-药物缀合物，其中市售的化疗药物苯丁酸氮芥、美法仑、氟替卡松、氨鲁米特和去氧氟尿苷通过各种键分别与二氢青蒿素（DHA）键合。其中，青蒿素-美法仑偶联物ARS 4对人卵巢癌细胞表现出最大的毒性，但对正常细胞的细胞毒性较低。ARS 4抑制卵巢癌细胞的生长和增殖，导致S期阻滞、细胞凋亡和迁移抑制;这些作用比其母体药物DHA和美法仑更强。此外，ARS 4调节参与细胞周期进程、凋亡和上皮-间质转化（EMT）的蛋白质的表达。此外，在小鼠中，ARS 4抑制卵巢癌细胞的生长和腹膜内传播和转移，而没有观察到毒性作用。我们的研究结果提供了一个基础的发展作为化疗药物的化合物。青蒿素类化合物由于其临床安全性和广泛的疗效，最近作为抗癌剂受到关注。然而，它们的治疗效力受到低溶解度和差生物利用度的限制。在这里，我们报告，ARS 4，青蒿素-美法仑共轭物，具有显着的体外和体内抗卵巢癌的抗肿瘤活性，其效果比其母体药物，双氢青蒿素和美法仑更强。在小鼠中，ARS 4抑制卵巢癌细胞的局部生长和腹膜内传播和转移，而没有明显的宿主毒性。因此，对于卵巢癌患者，ARS 4是一种有前途的化疗药物。通过药效团杂交策略设计青蒿素-药物偶联物ARS 4诱导卵巢癌细胞凋亡和细胞周期阻滞，逆转EMT极性在小鼠中，ARS 4抑制卵巢癌细胞的生长和腹腔内扩散，而没有明显的宿主毒性
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 epithelial–mesenchymal 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. 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 in-vitro 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. Artemisinin-drug conjugates were designed via pharmacophore hybridization strategy ARS4 induced apoptosis of ovarian cancer cells and cell cycle arrest and reversed the EMT polarity In mice, ARS4 inhibited growth and intraperitoneal dissemination of ovarian cancer cells with no appreciable host toxicity
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影响因子：
3.5
作者：
Blazquez, Alba G.;Fernandez-Dolon, Manuel;Romero, Marta R.
通讯作者：
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影响因子：
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影响因子：
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作者：
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