Plos One, 2013, 8(1):e50175.

Genistein Sensitizes Bladder Cancer Cells to HCPT Treatment In Vitro and In Vivo via ATM/NF-kB/IKK Pathway-Induced Apoptosis

Yong Wang, He Wang, Wei Zhang, et al

Department of Urology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China; et al

Bladder cancer is the most common malignant urological disease in China. Hydroxycamptothecin (HCPT) is a DNA topoisomerase I inhibitor, which has been utilized in chemotherapy for bladder cancer for nearly 40 years. Previous research has demonstrated that the isoflavone, genistein, can sensitize multiple cancer cell lines to HCPT treatment, such as prostate and cervical cancer. In this study, we investigated whether genistein could sensitize bladder cancer cell lines and bladder epithelial cell BDEC cells to HCPT treatment, and investigated the possible underlying molecular mechanisms. Genistein could significantly and dose-dependently sensitize multiple bladder cancer cell lines and BDEC cells to HCPT-induced apoptosis both in vitro and in vivo. Genistein and HCPT synergistically inhibited bladder cell growth and proliferation, and induced G2/M phase cell cycle arrest and apoptosis in TCCSUP bladder cancer cell and BDEC cell. Pretreatment with genistein sensitized BDEC and bladder cancer cell lines to HCPT-induced DNA damage by the synergistic activation of ataxia telangiectasia mutated (ATM) kinase. Genistein significantly attenuated the ability of HCPT to induce activation of the anti-apoptotic NF-κB pathway both in vitro and in vivo in a bladder cancer xenograft model, and thus counteracted the anti-apoptotic effect of the NF-κB pathway. This study indicates that genistein could act as a promising non-toxic agent to improve efficacy of HCPT bladder cancer chemotherapy.

美国《公共科学图书馆一》，2013年1月

金雀异黄素通过 ATM/NF-kB/IKK 通路诱导的细胞凋亡使体外和体内膀胱癌细胞对HCPT治疗更敏感

王勇，王和，张伟，等

中国陕西省西安市第四军医大学唐都医院泌尿科等

在中国，膀胱移行细胞癌是最常见的恶性泌尿系统疾病。羟基喜树碱 (HCPT) 是一种 DNA 拓扑异构酶I抑制剂，已被用于化疗治疗膀胱癌近 40 年。先前的研究表明异黄酮，金雀异黄素，可以使多种癌细胞如前列腺癌和宫颈癌等对HCPT治疗敏感。在此研究中，我们研究了金雀异黄素是否能提高膀胱癌细胞和膀胱上皮细胞 BDEC对羟基喜树碱治疗的敏感性，并探究其中可能的分子机制。金雀异黄素能明显并剂量依赖性地使多种膀胱癌细胞和 BDEC 细胞对羟基喜树碱在体外和体内诱导的细胞凋亡更加敏感。在TCCSUP 膀胱癌细胞和 BDEC细胞中，金雀异黄素和羟基喜树碱协同抑制膀胱癌细胞的生长和增殖，并诱导 G2/M 期细胞周期阻滞和细胞凋亡。金雀异黄素预处理通过协同共济失调毛细血管扩张症突变 (ATM) 激酶的活化使 BDEC 和膀胱肿瘤细胞对羟基喜树碱诱导的 DNA 损伤更敏感。在膀胱癌裸鼠移植瘤模型中，金雀异黄素显著减弱了羟基喜树碱诱导的体内和体外的抗凋亡 NF-κ B 通路活化的能力，从而抑制 NF-κ B 通路的抗凋亡作用。这项研究表明，金雀异黄素可作为有前途的无毒药物，以改善羟基喜树碱对膀胱癌症化疗的疗效。