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

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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.