Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, U.S.A.
Anticancer Res. 2014 Dec;34(12):6981-9.
Positive transcription elongation factor-b (P-TEFb) is a complex containing CDK9 and a cyclin (T1, T2 or K). The effect of inhibition of P-TEFb by 5,6-dichloro-l-β-D-ribofuranosyl benzimidazole (DRB) on cell radiosensitivity and the underlying mechanisms were investigated.
Six human cancer cell lines were subjected to (3)H-uridine incorporation, cell viability and clonogenic cell survival assays; cell-cycle redistribution and apoptosis assay; western blots and nuclear 53BP1 foci analysis after exposing the cells to DRB with/without γ-radiation.
DRB suppressed colony formation and enhanced radiosensitivity of all cell lines. DRB caused a further increase in radiation-induced apoptosis and cell-cycle redistribution depending on p53 status. DRB prolonged the presence of radiation-induced nuclear p53 binding protein-1 (53BP1) foci and suppressed the expression of sirtuin-1 (SIRT1) and casein kinase 2-alpha (CK2α), suggesting an inhibition of DNA repair processes.
Our findings indicate that DRB has the potential to increase the efficacy of radiotherapy and warrants further investigation using in vivo tumor models.
正转录延伸因子-b（P-TEFb）是一种包含 CDK9 和细胞周期蛋白（T1、T2 或 K）的复合物。本研究旨在探讨抑制 P-TEFb 对细胞放射敏感性的影响及其潜在机制。
采用放射性标记尿嘧啶掺入法、细胞活力和集落形成实验、细胞周期分布和凋亡实验、Western blot 和核 53BP1 焦点分析等方法，检测 DRB 联合或不联合γ射线处理后 6 个人类癌细胞系的上述指标。
DRB 抑制了所有细胞系的集落形成并增强了其放射敏感性。DRB 可根据 p53 状态进一步增加辐射诱导的细胞凋亡和细胞周期分布改变。DRB 延长了辐射诱导的核 p53 结合蛋白-1（53BP1）焦点的存在时间，并抑制了沉默信息调节因子 1（SIRT1）和酪蛋白激酶 2-α（CK2α）的表达，提示其抑制了 DNA 修复过程。
DRB 具有提高放射治疗效果的潜力，值得进一步研究，包括使用体内肿瘤模型进行研究。
