Novel artemisinin derivatives with potential usefulness against liver/colon cancer and viral hepatitis
Novel artemisinin derivatives with potential usefulness against liver/colon cancer and viral hepatitis
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DOI：
10.1016/j.bmc.2013.04.059
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发表时间：
2013-07-15
影响因子：
3.5
通讯作者：
Romero, Marta R.
中科院分区：
文献类型：
--
作者：
Blazquez, Alba G.;Fernandez-Dolon, Manuel;Romero, Marta R.
抗疟药青蒿素的抗肿瘤和抗病毒特性已被报道。新的青蒿素衍生物（AD 1-AD 8）已经被合成并使用肝/结肠癌和病毒性肝炎B和C的体外模型进行评价。在用AD 1-AD 8处理来自肝母细胞瘤（HepG 2）、肝癌（SK-HEP-1）和结肠腺癌（LS 174 T）的人细胞系短（6小时）和长（72小时）时间后的细胞活力测定显示，AD 5结合了低急性毒性和高抗增殖作用（IC 50 = 1-5 μ M）。由于铁介导的过氧键活化参与青蒿素抗疟活性，铁（II）-甘氨酸硫酸盐（铁烷醇）和含铁（III）的原卟啉IX（氯化血红素）的影响进行了研究。如果细胞预先加入AD 5，铁烷醇而非氯化血红素可增强AD 5的抗增殖活性，但如果两种化合物一起加入则无此作用。5个衍生物（AD 1> AD 2> AD 7> AD 3> AD 8）能够抑制牛病毒性腹泻病毒（BVDV）的细胞病变效应，BVDV是丙型肝炎病毒（HCV）的体外替代模型，用于评价抗黄病毒的活性。此外，AD 1和AD 2抑制BVDV-RNA释放到培养基中。与氯化血红素或铁烷醇的共处理导致AD 1的抗黄病毒活性增强。在用B肝炎病毒（HBV）永久感染的HepG 2细胞中，在对宿主细胞无毒的浓度下，AD 1和AD 4能够减少HBV-DNA向培养基的释放。总之，青蒿素相关新药具有很高的药理学价值，值得在动物模型中进一步评价，这些药物可能用于治疗肝癌和病毒性肝炎B和C。(C)2013爱思唯尔有限公司保留所有权利。
Antitumor and antiviral properties of the antimalaria drug artemisinin from Artemisia annua have been reported. Novel artemisinin derivatives (AD1-AD8) have been synthesized and evaluated using in vitro models of liver/colon cancer and viral hepatitis B and C. Cell viability assays after treating human cell lines from hepatoblastoma (HepG2), hepatocarcinoma (SK-HEP-1), and colon adenocarcinoma (LS174T) with AD1-AD8 for a short (6 h) and long (72 h) period revealed that AD5 combined low acute toxicity together with high antiproliferative effect (IC50 = 1-5 mu M). Since iron-mediated activation of peroxide bond is involved in artemisinin antimalarial activity, the effect of iron(II)-glycine sulfate (ferrosanol) and iron(III)-containing protoporphyrin IX (hemin) was investigated. Ferrosanol, but not hemin, enhanced antiproliferative activity of AD5 if the cells were preloaded with AD5, but not if both compouds were added together. Five derivatives (AD1 > AD2 > AD7 > AD3 > AD8) were able to inhibit the cytopathic effect of bovine viral diarrhoea virus (BVDV), a surrogate in vitro model of hepatitis C virus (HCV), used here to evaluate the anti-Flaviviridae activity. Moreover, AD1 and AD2 inhibited the release of BVDV-RNA to the culture medium. Co-treatment with hemin or ferrosanol resulted in enhanced anti-Flaviviridae activity of AD1. In HepG2 cells permanently infected with hepatitis B virus (HBV), AD1 and AD4, at non-toxic concentrations for the host cells were able to reduce the release of HBV-DNA to the medium. In conclusion, high pharmacological interest deserving further evaluation in animal models has been identified for novel artemisinin-related drugs potentially useful for the treatment of liver cancer and viral hepatitis B and C. (C) 2013 Elsevier Ltd. All rights reserved.