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.
Highlights
Ovarian cancer is the leading cause of death by gynecological malignancies
The two NSAIDs had different effects on the cell cycle, as diclofenac induced an accumulation of cells at S phase and G2, while indomethacin induced G1 arrest in all three ovarian cancer cell lines examined
We observed a sub-G1 population of cells in the UCI-101 cells treated with diclofenac and indomethacin and in HEY cells treated with indomethacin, suggesting increased apoptosis
Summary
Ovarian cancer is the leading cause of death by gynecological malignancies. When detected early, the 5-year survival rate is as high as 90%, but the vast majority of cases are diagnosed as late-stage disease, which is often resistant to conventional chemotherapy. The NSAID diclofenac decreased the growth of pancreatic and non-small cell lung cancer xenografts [10,11]. There are limited preclinical studies investigating the effects and mechanisms of action of diclofenac and indomethacin in ovarian cancer [12,13]. In this regard, Zerbini et al reported that diclofenac decreased tumor volume in SCID mice with ovarian cancer cell SKOV-3 xenografts by ,20% [12]. Another study reported that indomethacin had no effect on the growth of ovarian reticular cell sarcoma M5076 [13]
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