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

Abstract

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.

The Effects of Cytotoxic Dose of Diclofenac on CD82/KAI1 in Cervical Cancer Cells in Cell Culture

“…Previous studies also have shown that NSAIDs diclofenac exerts an antiproliferative effect in ovarian cancer in vitro and in vivo and the effects of NSAIDs may be mediated, in part, by downregulation of E2F1. [11] In contrast to our finding, further studies are warranted regarding the potential benefit of diclofenac and other NSAIDs to improve some types of cancers. [12] , [13] Cervical cancer is associated with abnormal expression of multiple genes.…”

Proteasome Inhibition Increases Recruitment of IκB Kinase β (IKKβ), S536P-p65, and Transcription Factor EGR1 to Interleukin-8 (IL-8) Promoter, Resulting in Increased IL-8 Production in Ovarian Cancer Cells

“…In addition, recent studies have suggested that anti-inflammatory therapy may enhance the cytotoxicity of platinum drugs and proteasome inhibitors in ovarian carcinoma (71)(72)(73). Findings in this study indicate that the increased expression and release of IL-8 induced by proteasome inhibition may represent one of the mechanisms responsible for the decreased effectiveness of BZ in ovarian cancer treatment and identify IKK␤ and EGR-1 as potential new targets in ovarian cancer combination therapies.…”

IL-1β-Mediated Repression of microRNA-101 Is Crucial for Inflammation-Promoted Lung Tumorigenesis

“…Recent studies found that NSAIDs may exert anticancer activities in both COX-dependent and -independent manners, including suppressing E2F1, Mcl-1, and survivin and activating the eIF2a kinase PKR in various cancer cells (12,47,48). Nevertheless, whether miRNA regulation is involved in the anticancer actions of NSAIDs remained largely unexplored.…”