Drug and Chemical Toxicology, 2013, 36(2):196-204.

Inhibition of proliferation and induction of G1-phase cell-cycle arrest by dFMGEN, a novel genistein derivative, in lung carcinoma A549 cells

Bo Peng, Jiangguo Cao, Sisi Yi, et al

Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China

Genistein (GEN) is a molecule of great interest as a potent chemopreventive agent against atherosclerosis and cancer. However, the bioavailability of GEN is very low in vivo. Our previous study showed that a GEN derivative, 7-difluoromethyl-5,4'-dimethoxygenistein (dFMGEN) has a better bioavailability than GEN in vivo. In this study, we further evaluated the efficacy of dFMGEN as a candidate for cancer therapy. We demonstrated that dFMGEN treatment decreased the viability of A549 cells in a concentration- and time-dependent manner and induced cell-cycle arrest at the G(1) phase. G(1) phase arrest was correlated with a significant reduction of Cdk4 and cyclin D1 protein level. Further studies showed that cyclin-dependent kinase (Cdk)4 and cyclin D1 protein-level decrease was caused by Cdk inhibitors p15, p21, and p27 level increase, and decreased protein level directly suppressed Rb protein phosphorylation and E2F-1 expression, then cell-cycle progression was arrested. Finally, we also found that dFMGEN has a dosage effect in suppressing tumor growth in vivo, and that dFMGEN was well tolerated by animals. In summary, our results suggest that dFMGEN has therapeutic potential for the treatment of human lung cancer.

英国《药物和化学毒物学》，2013年4月

在肺癌 A549 细胞中可以抑制细胞增殖并诱导 G1 期细胞周期中止的dFMGEN，是一种新型金雀异黄素衍生物

彭博，曹建国，伊思思，等

中国长沙中南大学湘雅医学院癌症研究所

金雀异黄素 （GEN） 作为一种强效的化学预防动脉粥样硬化和癌症的药剂引起了极大的兴趣。然而，GEN在体内的生物利用度非常低。我们先前的研究表明，一种金雀异黄素衍生物，7-二氟甲基-5,4'-二甲氧基金雀异黄素 (dFMGEN) 在体内具有比GEN更好的生物利用度。在此研究中，我们进一步评价了dFMGEN 作为癌症治疗方法的疗效。我们证明了 dFMGEN 的疗法以浓度和时间依赖性的方式降低 了A549 细胞的存活性，并且诱导细胞周期在 G(1) 期阻滞。G(1)期阻滞与 Cdk4 和细胞周期蛋白 D1 蛋白水平明显降低有关。进一步研究表明，细胞周期蛋白依赖性激酶 (Cdk) 4 和细胞周期蛋白 D1 蛋白水平下降由蛋白激酶抑制剂 p15、 p21 和 p27 水平升高造成，降低的蛋白质水平直接抑制了 Rb 蛋白磷酸化和 E2F-1 的表达，然后细胞周期进程被中止。最后，我们还发现，dFMGEN 在抑制体内肿瘤生长时具有剂量效应，并且 dFMGEN 可以被动物很好的耐受。总之，我们的结果表明，dFMGEN 具有治疗人体肺癌的潜力。