Non-Steroidal Anti-inflammatory Drugs Decrease E2F1 Expression and Inhibit Cell Growth in Ovarian Cancer Cells

Epidemiological studies have shown that the regular use of non-steroidal anti-inflammatory (NSAIDs) drugs is associated with a reduced risk of various cancers. In addition, in vitro and experiments in mouse models have demonstrated that NSAIDs decrease tumor initiation and/or progression of several cancers. However, there are limited preclinical studies investigating the effects of NSAIDs in ovarian cancer. Here, we have studied the effects of two NSAIDs, diclofenac and indomethacin, in ovarian cancer cell lines and in a xenograft mouse model. Diclofenac and indomethacin treatment decreased cell growth by inducing cell cycle arrest and apoptosis. In addition, diclofenac and indomethacin reduced tumor volume in a xenograft model of ovarian cancer. To identify possible molecular pathways mediating the effects of NSAID treatment in ovarian cancer, we performed microarray analysis of ovarian cancer cells treated with indomethacin or diclofenac. Interestingly, several of the genes found downregulated following diclofenac or indomethacin treatment are transcriptional target genes of E2F1. E2F1 was downregulated at the mRNA and protein level upon treatment with diclofenac and indomethacin, and overexpression of E2F1 rescued cells from the growth inhibitory effects of diclofenac and indomethacin. In conclusion, NSAIDs diclofenac and indomethacin exert an anti-proliferative effect in ovarian cancer in vitro and in vivo and the effects of NSAIDs may be mediated, in part, by downregulation of E2F1.

流行病学研究表明，规律服用非甾体抗炎药（non-steroidal anti-inflammatory drugs，NSAIDs）与多种癌症的发病风险降低相关。此外，体外实验与小鼠模型实验均证实，非甾体抗炎药可抑制多种癌症的肿瘤起始及/或进展过程。然而，针对非甾体抗炎药在卵巢癌中作用的临床前研究仍较为匮乏。本研究针对两种非甾体抗炎药——双氯芬酸与吲哚美辛，在卵巢癌细胞系及异种移植小鼠模型中的作用展开探究。结果显示，双氯芬酸与吲哚美辛可通过诱导细胞周期阻滞与细胞凋亡抑制细胞增殖，同时可降低卵巢癌异种移植模型的肿瘤体积。为明确介导非甾体抗炎药抗卵巢癌作用的潜在分子通路，本研究对经吲哚美辛或双氯芬酸处理的卵巢癌细胞进行了基因芯片分析。有趣的是，双氯芬酸或吲哚美辛处理后下调的诸多基因均为E2F1的转录靶基因。进一步检测发现，经双氯芬酸与吲哚美辛处理后，E2F1在信使RNA（messenger RNA，mRNA）与蛋白水平均出现下调；而过表达E2F1则可挽救细胞免受双氯芬酸与吲哚美辛的生长抑制作用。综上，非甾体抗炎药双氯芬酸与吲哚美辛在体外及体内均可对卵巢癌发挥抗增殖效应，其作用机制可能部分通过下调E2F1实现。