Sophoranone, extracted from a traditional Chinese medicine Shan Dou Gen, induces apoptosis in human leukemia U937 cells via formation of reactive oxygen species and opening of mitochondrial permeability transition pores.
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 roots of Sophora subprostrata Chun et T. Chen. We purified the compound that induced apoptosis 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 microM. 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 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.
The Laboratories of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
Sachiko
S
Kajimoto
Noriko
N
Takanashi
Tetsuya
T
Kajimoto
Man
M
Xu
Judong
J
Cao
Yutaka
Y
Masuda
Toshihiro
T
Aiuchi
Shigeo
S
Nakajo
Yoshiteru
Y
Ida
Kazuyasu
K
Nakaya
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D003574:Cytochrome c Group / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000494:pharmacology*; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008516:Medicine, Chinese Traditional; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D010539:Permeability; D010946:Plants, Medicinal / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D020298:U937 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D003574:Cytochrome c Group; D004273:DNA, Neoplasm; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D017382:Reactive Oxygen Species; C461819:sophoranone; D013481:Superoxides