title: Apoptosis induced by 7-difluoromethoxyl-5,4'-di-n-octyl genistein via             the inactivation of FoxM1 in ovarian cancer cells.
abstract: Genistein, 5,7,4'-trihydroxylisoflavone, a major component of soybean products, has been reported to possess anticancer activities. We examined the antitumor effects of 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), a novel synthetic genistein derivative, on human ovarian cancer cells as well as the molecular mechanism. The growth-inhibitory effects of genistein and DFOG were determined using MTT assay and clonogenic assay in CoC1 and SKOV3 human ovarian cancer cells. Apoptotic activities of DFOG were observed using histone/DNA ELISA assay and flow cytometry with propidium iodide (PI) staining. Multiple molecular techniques, such as RT-PCR, western blot analysis, siRNA and cDNA transfection were used to explore the molecular mechanism. We demonstrated that nine of the genistein derivatives had a more effective antitumor activity than genistein. Among the afore-mentioned derivatives, DFOG presented with the strongest activity against CoC1 and SKOV3 cells in vitro. DFOG and genistein inhibited the growth of CoC1 and SKOV3 cells, accompanied by cell cycle arrest in the G2/M phase. DFOG caused apoptotic cell death with concomitant attenuation of Forkhead box protein M1 (FoxM1) and its downstream genes, such as survivin, cdc25B, cyclin B, and increased p27KIP1. Downregulation of FoxM1 by siRNA followed by DFOG treatment resulted in enhanced cell growth inhibition and induction of apoptosis. Upregulation of FoxM1 by cDNA transfection attenuated DFOG-induced cell growth inhibition and apoptotic cell death. Our results show that the molecular role of FoxM1 in mediating the biological effects of DFOG and genistein in human ovarian cancer cells suggests that FoxM1 could be a novel target for the treatment of human ovarian cancer.
authors.affiliation: The First Affiliated Hospital of Guangzhou Medical college, Guangzhou 510120, PR China.
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Ning
authors.forename: Qingxiu
authors.initials: Q
authors.lastname: Li
authors.forename: Honglin
authors.initials: H
authors.lastname: Xiang
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Jianguo
authors.initials: J
authors.lastname: Cao
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019926:Cyclin B / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D019833:Genistein / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D000077022:Survivin; D020687:cdc25 Phosphatases / Q000096:biosynthesis
chemical_list: C541079:7-difluoromethyl-5,4'-dimethoxygenistein; C107489:BIRC5 protein, human; C436291:CDKN1B protein, human; D019926:Cyclin B; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019833:Genistein; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases