PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells.
PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells.
复制标题
DOI：
10.3892/or.2016.4653
复制
发表时间：
2016-05
期刊：
影响因子：
4.2
通讯作者：
Kikkawa F
中科院分区：
文献类型：
--
作者：
Yoshikawa N;Kajiyama H;Nakamura K;Utsumi F;Niimi K;Mitsui H;Sekiya R;Suzuki S;Shibata K;Callen D;Kikkawa F
上皮性卵巢癌（EOC）是妇科恶性肿瘤中最致命的一种，由于其高复发率，因此迫切需要开发治疗EOC的新药。TP 53突变是EOC中的常见事件，特别是在高级别浆液性卵巢癌中，超过90%的病例发生TP 53突变。最近，PRIMA-1和PRIMA-1 MET（p53再活化和诱导大量凋亡及其甲基化形式）显示对几种类型的癌症具有抗肿瘤作用。尽管PRIMA-1 MET是第一个在临床试验中评估的化合物，但PRIMA-1 MET对EOC的抗肿瘤作用仍不清楚。在这项研究中，我们研究了PRIMA-1 MET治疗EOC细胞的治疗潜力。PRIMA-1 MET处理EOC细胞系（n=13）导致不同浓度（24 h IC 50 2.6-20.1 µM）的快速凋亡。凋亡反应是独立的p53状态和化学敏感性。PRIMA-1 MET处理增加细胞内活性氧（ROS），PRIMA-1 MET诱导的细胞凋亡被ROS清除剂拯救。此外，RNA表达分析显示，PRIMA-1 MET的作用机制可能是由于抑制抗氧化酶，如Prx 3和GPx-1。总之，我们的研究结果表明，PRIMA-1 MET代表了一种新的治疗策略，用于治疗卵巢癌，而不考虑p53状态和化疗敏感性。
There is an intensive need for the development of novel drugs for the treatment of epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy due to the high recurrence rate. TP53 mutation is a common event in EOC, particularly in high-grade serous ovarian cancer, where it occurs in more than 90% of cases. Recently, PRIMA-1 and PRIMA-1MET (p53 reactivation and induction of massive apoptosis and its methylated form) were shown to have an antitumor effect on several types of cancer. Despite that PRIMA-1MET is the first compound evaluated in clinical trials, the antitumor effects of PRIMA-1MET on EOC remain unclear. In this study, we investigated the therapeutic potential of PRIMA-1MET for the treatment of EOC cells. PRIMA-1MET treatment of EOC cell lines (n=13) resulted in rapid apoptosis at various concentrations (24 h IC50 2.6–20.1 µM). The apoptotic response was independent of the p53 status and chemo-sensitivity. PRIMA-1MET treatment increased intracellular reactive oxygen species (ROS), and PRIMA-1MET-induced apoptosis was rescued by an ROS scavenger. Furthermore, RNA expression analysis revealed that the mechanism of action of PRIMA-1MET may be due to inhibition of antioxidant enzymes, such as Prx3 and GPx-1. In conclusion, our results suggest that PRIMA-1MET represents a novel therapeutic strategy for the treatment of ovarian cancer irrespective of p53 status and chemo-sensitivity.