Princess Margaret Hospital, Ontario Cancer Institute, Toronto, ON, Canada.
Blood. 2010 Nov 4;116(18):3593-603. doi: 10.1182/blood-2010-01-262675. Epub 2010 Jul 19.
To identify known drugs with previously unrecognized anticancer activity, we compiled and screened a library of such compounds to identify agents cytotoxic to leukemia cells. From these screens, we identified ivermectin, a derivative of avermectin B1 that is licensed for the treatment of the parasitic infections, strongyloidiasis and onchocerciasis, but is also effective against other worm infestations. As a potential antileukemic agent, ivermectin induced cell death at low micromolar concentrations in acute myeloid leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. Ivermectin also delayed tumor growth in 3 independent mouse models of leukemia at concentrations that appear pharmacologically achievable. As an antiparasitic, ivermectin binds and activates chloride ion channels in nematodes, so we tested the effects of ivermectin on chloride flux in leukemia cells. Ivermectin increased intracellular chloride ion concentrations and cell size in leukemia cells. Chloride influx was accompanied by plasma membrane hyperpolarization, but did not change mitochondrial membrane potential. Ivermectin also increased reactive oxygen species generation that was functionally important for ivermectin-induced cell death. Finally, ivermectin synergized with cytarabine and daunorubicin that also increase reactive oxygen species production. Thus, given its known toxicology and pharmacology, ivermectin could be rapidly advanced into clinical trial for leukemia.
为了鉴定具有先前未知抗癌活性的已知药物，我们编译并筛选了此类化合物库，以鉴定对白血病细胞具有细胞毒性的药物。从这些筛选中，我们发现了伊维菌素，它是阿维菌素 B1 的衍生物，已获得许可用于治疗寄生虫感染、旋毛虫病和盘尾丝虫病，但对其他寄生虫感染也有效。作为一种潜在的抗白血病药物，伊维菌素在急性髓系白血病细胞系和原发性患者样本中以低微摩尔浓度诱导细胞死亡，优先于正常造血细胞。伊维菌素还以在药理学上可实现的浓度延迟了 3 种独立的白血病小鼠模型中的肿瘤生长。作为一种驱虫药，伊维菌素结合并激活线虫中的氯离子通道，因此我们测试了伊维菌素对白血病细胞中氯离子通量的影响。伊维菌素增加了白血病细胞中的氯离子浓度和细胞体积。氯离子内流伴随着质膜超极化，但不改变线粒体膜电位。伊维菌素还增加了活性氧的产生，这对于伊维菌素诱导的细胞死亡是功能上重要的。最后，伊维菌素与阿糖胞苷和柔红霉素协同作用，柔红霉素也增加活性氧的产生。因此，鉴于其已知的毒理学和药理学，伊维菌素可以迅速进入白血病的临床试验。
