Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, China.
Drug Chem Toxicol. 2013 Apr;36(2):196-204. doi: 10.3109/01480545.2012.710620. Epub 2012 Aug 30.
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.
染料木黄酮（GEN）是一种具有强大化学预防作用的抗动脉粥样硬化和癌症的分子。然而，GEN 的生物利用度在体内非常低。我们之前的研究表明，GEN 的一种衍生物，7-二氟甲基-5,4'-二甲氧基染料木黄酮（dFMGEN）在体内的生物利用度优于 GEN。在这项研究中，我们进一步评估了 dFMGEN 作为癌症治疗候选药物的疗效。我们证明，dFMGEN 处理以浓度和时间依赖的方式降低 A549 细胞的活力，并诱导细胞周期停滞在 G1 期。G1 期停滞与 Cdk4 和细胞周期蛋白 D1 蛋白水平的显著降低相关。进一步的研究表明，细胞周期蛋白依赖性激酶（Cdk）4 和细胞周期蛋白 D1 蛋白水平的降低是由于 Cdk 抑制剂 p15、p21 和 p27 水平的增加引起的，并且降低的蛋白水平直接抑制了 Rb 蛋白磷酸化和 E2F-1 的表达，从而使细胞周期停滞。最后，我们还发现 dFMGEN 在体内抑制肿瘤生长方面具有剂量效应，并且动物对 dFMGEN 具有良好的耐受性。总之，我们的结果表明，dFMGEN 具有治疗人类肺癌的潜力。
