Studies on apoptosis-inducers targeted for the molecules associated with the induction of apoptosis in cancer cells

在寻找新的人类白血病细胞凋亡诱导剂的过程中，通过对各种天然产物的筛选，我们鉴定了中药山豆根的甲醇提取物具有很强的诱导细胞凋亡的活性，山豆根是从苦豆根中分离出来的，用作解毒剂和止痛药。我们纯化了在人类白血病细胞中诱导的化合物，并将其鉴定为苦参酮。苦参酮对人实体瘤细胞株具有明显的抑制细胞生长和诱导细胞凋亡的作用，对人胃癌MKN7细胞的生长抑制率为(1.2±0.3)μM。苦参酮对白血病U937细胞的生长抑制和诱导凋亡作用明显强于其他黄酮类化合物，如大豆苷元、染料木素和槲皮素。在苦参酮作用U937细胞的早期，细胞内产生了活性氧，线粒体通透性开孔，细胞色素c从线粒体中释放出来。用苦参酮处理分离的线粒体后，细胞色素c也被释放。线粒体呼吸链的复合体III和IV的抑制剂，而不是复合体I和II的抑制剂，可以阻止苦参酮从分离的线粒体释放细胞色素c，以及诱导U937细胞对苦参酮的诱导凋亡。我们的结果表明，苦参酮可能是一种独特的以线粒体为靶点的诱导细胞凋亡的抗癌药物。

Screening of various natural products in a search for novel inducers of apoptosis in human leukemia cells led us to identify the strong apoptosis-inducing activity in a fraction extracted with methanol from the traditional Chinese medicine Shan Dou Gen, which is isolated from the roots of Sophora subprostrata Chun et T.Chen and is used as an antidote and an anodyne. We purified the compound that induced in human leukemia cells and identified it as sophoranone. Sophoranone inhibited cell growth and induced apoptosis in various lines of cells from human solid tumors, with 50% inhibition of growth of human stomach cancer MKN7 cells at 1.2±0.3 μM.The growth-inhibitory and apoptosis-inducing activities of sophoranone for leukemia U937 cells were very much stronger than those of other flavonoids, such as daidzein, genistein, and quercetin. At the early stages of treatment of U937 cells with sophoranone, reactive oxygen species (ROS) were formed, mitochondrial permeability pores were opened, and cytochrome c was released from mitochondria. Cytochrome c was also released upon treatment of isolated mitochondria with sophoranone. Inhibitors of complexes III and IV, but not complexes I and II, of the mitochondrial respiratory chain prevented the release of cytochrome c from isolated mitochondria by sophoranone, as well as the induction of apoptosis in U937 cells in response to sophoranone. Our results indicate that sophoranone might be a unique apoptosis-inducing anticancer agent that targets mitochondria.