Oncology Reports, 2012, 27(6):1857-1864.

Apoptosis induced by 7-difluoromethoxyl-5,4'-di-n-octyl genistein via the inactivation of FoxM1 in ovarian cancer cells

Yingxia Ning, Qingxiu Li, Honglin Xiang, et al

The First Affiliated Hospital of Guangzhou Medical college, Guangzhou 510120, PR China

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.

希腊《肿瘤学报告》，2012年6月

在卵巢癌中7-二氟甲氧基-5,4'-二-正辛烷氧基 金雀异黄素通过 FoxM1细胞失活诱导细胞凋亡

宁映霞，李清秀，向红林等

中国广州广州医学院第一附属医院

金雀异黄素，5，7，4'-三羟基异黄酮，是大豆产物的主要成分，据报道说具有抗癌活性。我们测试了7-二氟甲氧基-5,4'-二-正辛烷氧基 金雀异黄素(DFOG)，一种人工合成的新型金雀异黄素衍生物，对卵巢癌细胞的分子作用机制。金雀异黄素和 DFOG 的生长抑制作用通过在 CoC1 和 SKOV3 卵巢癌中的MTT 法和克隆试验测定。用组蛋白/ DNA 酶联免疫吸附法和流式细胞术与丙啶 (PI) 碘染色观察DFOG的细胞凋亡活性。多种分子技术，例如RT-PCR、 免疫印迹分析， siRNA 和 cDNA 转染法，被用来探索分子机制。我们证明了九种金雀异黄素衍生物具有比金雀异黄素更有效的抗肿瘤活性。在之前提到的衍生物种，DFOG 表现出对体外CoC1 和 SKOV3 细胞的最强活性。DFOG 和金雀异黄素抑制 CoC1 和 SKOV3 细胞的生长，伴有细胞周期在 G2/M 期阻滞。DFOG 会引起细胞凋亡，并伴随着蛋白 M1 (FoxM1) 及其下游基因，比如生存素、 cdc25B、 细胞周期蛋白 B 和增加的 p27KIP1的衰减。FoxM1由siRNA下调，然后 DFOG 治疗会导致细胞生长抑制和诱导细胞凋亡的作用增强。FoxM1由cDNA转染上调，会减弱DFOG 诱导的细胞生长抑制和凋亡性细胞死亡。我们的研究结果表明了 FoxM1在 介导 DFOG 和金雀异黄素对卵巢癌细胞生物学效应的分子作用，并且FoxM1 可能是卵巢癌治疗的新靶点。