Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Cancer Lett. 2012 Dec 1;325(1):35-41. doi: 10.1016/j.canlet.2012.05.020. Epub 2012 May 22.
We evaluated whether the restoration of p53 function by the p53-reactivating small molecule RITA (reactivation of p53 and induction of tumor cell apoptosis enhances cisplatin-induced cytotoxicity and apoptosis in head-and-neck cancer (HNC). RITA induced prominent accumulation and reactivation of p53 in a wild-type TP53-bearing HNC cell line. RITA showed maximal growth suppression in tumor cells showing MDM2-dependent p53 degradation. RITA promoted apoptosis in association with upregulation of p21, BAX, and cleaved caspase-3; notably, the apoptotic response was blocked by pifithrin-α, demonstrating its p53 dependence. With increasing concentrations, RITA strongly induced apoptosis rather than G2-phase arrest. In combination therapy, RITA enhanced cisplatin-induced growth inhibition and apoptosis of HNC cells invitro and in vivo. Our data suggest that the restoration of p53 tumor-suppressive function by RITA enhances the cytotoxicity and apoptosis of cisplatin, an action that may offer an attractive strategy for treating HNC.
我们评估了通过 p53 激活小分子 RITA（p53 的重新激活和诱导肿瘤细胞凋亡）恢复 p53 功能是否增强了头颈部癌症（HNC）中顺铂诱导的细胞毒性和细胞凋亡。RITA 诱导了野生型 TP53 携带的 HNC 细胞系中 p53 的明显积累和重新激活。RITA 在显示 MDM2 依赖性 p53 降解的肿瘤细胞中显示出最大的生长抑制作用。RITA 通过上调 p21、BAX 和 cleaved caspase-3 促进细胞凋亡；值得注意的是，凋亡反应被 pifithrin-α 阻断，表明其依赖于 p53。随着浓度的增加，RITA 强烈诱导细胞凋亡而不是 G2 期阻滞。在联合治疗中，RITA 增强了顺铂诱导的 HNC 细胞在体外和体内的生长抑制和凋亡。我们的数据表明，RITA 恢复 p53 肿瘤抑制功能增强了顺铂的细胞毒性和细胞凋亡，这可能为治疗 HNC 提供了一种有吸引力的策略。
