Camphausen Kevin, Brady Kristin J, Burgan William E, Cerra Michael A, Russell Jeffery S, Bull Elizabeth E A, Tofilon Philip J
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
Mol Cancer Ther. 2004 Apr;3(4):409-16.
Flavopiridol is a cyclin-dependent kinase (CDK) inhibitor, which has recently entered clinical trials. However, when administered as a single agent against solid tumors, the antitumor actions of flavopiridol have been primarily cytostatic. Given its reported effects on cell cycle regulation, transcription, and apoptosis, flavopiridol may also influence cellular radioresponse. Thus, to evaluate the potential for combining this cyclin-dependent kinase inhibitor with radiation as a cancer treatment strategy, we have investigated the effects of flavopiridol on the radiation sensitivity of two human prostate cancer cell lines (DU145 and PC3). The data presented here indicate that exposure to flavopiridol (60-90 nM) after irradiation enhanced the radiosensitivity of both DU145 and PC3 cells. This sensitization occurred in the absence of significant reductions in cell proliferation, retinoblastoma protein phosphorylation, or P-TEFb activity. Moreover, the post-irradiation addition of flavopiridol had no effect on radiation-induced apoptosis or the activation of the G2 cell cycle checkpoint. However, flavopiridol did modify the time course of gammaH2AX expression in irradiated cells. Whereas there was no significant difference in radiation-induced gammaH2AX foci at 6 h, at 24 h after irradiation, the number of cells expressing gammaH2AX foci was significantly greater in the flavopiridol-treated cells. These results indicate that flavopiridol can enhance radiosensitivity of human tumor cells and suggest that this effect may involve an inhibition of DNA repair.
黄酮哌啶醇是一种细胞周期蛋白依赖性激酶（CDK）抑制剂，最近已进入临床试验阶段。然而，当作为单一药物用于实体瘤治疗时，黄酮哌啶醇的抗肿瘤作用主要是细胞生长抑制作用。鉴于其对细胞周期调控、转录和凋亡的报道作用，黄酮哌啶醇可能也会影响细胞的放射反应。因此，为了评估将这种细胞周期蛋白依赖性激酶抑制剂与放疗联合作为癌症治疗策略的潜力，我们研究了黄酮哌啶醇对两种人前列腺癌细胞系（DU145和PC3）放射敏感性的影响。此处呈现的数据表明，照射后暴露于黄酮哌啶醇（60 - 90 nM）可增强DU145和PC3细胞的放射敏感性。这种增敏作用发生时，细胞增殖、视网膜母细胞瘤蛋白磷酸化或P - TEFb活性均未显著降低。此外，照射后添加黄酮哌啶醇对辐射诱导的凋亡或G2细胞周期检查点的激活没有影响。然而，黄酮哌啶醇确实改变了照射细胞中γH2AX表达的时间进程。虽然在照射后6小时辐射诱导的γH2AX焦点没有显著差异，但在照射后24小时，黄酮哌啶醇处理的细胞中表达γH2AX焦点的细胞数量显著更多。这些结果表明，黄酮哌啶醇可增强人肿瘤细胞的放射敏感性，并提示这种作用可能涉及对DNA修复的抑制。
