The novel targets for anti-angiogenesis of genistein on human cancer cells.
Genistein has been reported to be a natural chemopreventive in several types of human cancer. In our prior study, soy isoflavones were shown to induce cell cycle arrest and apoptosis of bladder cancer cells in the range of human urine excretion. This study was designed to identify the novel molecular basis underlying anti-angiogenic activities of soy isoflavones. An immortalized E6 and five human bladder cancer cell lines were studied by immunoassay, flow cytometry, functional activity, reverse transcription-polymerase chain reaction, immunoblotting, and transwell co-culture in vitro. The efficacy of soy isoflavones on angiogenesis inhibition in vivo was examined by nude mice xenograft and chick chorioallantoic membrane bioassay. Factors analyzed included angiogenic factors, matrix-degrading enzymes, and angiogenesis inhibitors. Genistein was the most potent inhibitor of angiogenesis in vitro and in vivo among the isoflavone compounds tested. It may also account for most of the reduced microvessel density of xenografts observed and the suppressed endothelial migration by soy isoflavones. Genistein exhibited a dose-dependent inhibition of expression/excretion of vascular endothelial growth factor165, platelet-derived growth factor, tissue factor, urokinase plasminogen activator, and matrix metalloprotease-2 and 9, respectively. On the other hand, there was an up-regulation of angiogenesis inhibitors-plasminogen activator inhibitor-1, endostatin, angiostatin, and thrombospondin-1. In addition, a differential inhibitory effect between immortalized uroepithelial cells and most cancer cell lines was also observed. Altogether, we discovered that tissue factor, endostatin, and angiostatin are novel molecular targets of genistein. The current investigation provides further evidence in support of soy-based foods as natural dietary inhibitors of tumor angiogenesis.
Su
Shu-Jem
SJ
Department of Medical Technology, Fooyin University, Kaohsiung Hsien 831, Taiwan.
Yeh
Trai-Ming
TM
Chuang
Woei-Jer
WJ
Ho
Chung-Liang
CL
Chang
Kee-Lung
KL
Cheng
Hsiao-Ling
HL
Liu
Hsiao-Sheng
HS
Cheng
Hong-Lin
HL
Hsu
Pei-Yin
PY
Chow
Nan-Haw
NH
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D019833:Genistein / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D019833:Genistein