title: 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.
authors: Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, Maryland, United States of America.
authors: Blanca L
authors: BL
authors: Valle
authors: Theresa
authors: T
authors: D'Souza
authors: Kevin G
authors: KG
authors: Becker
authors: William H
authors: WH
authors: Wood
authors: Yongqing
authors: Y
authors: Zhang
authors: Robert P
authors: RP
authors: Wersto
authors: Patrice J
authors: PJ
authors: Morin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004008:Diclofenac / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D050687:E2F1 Transcription Factor; D004008:Diclofenac; D007213:Indomethacin
references: J Med Chem. 2004 Feb 12;47(4):999-1007
references: 14761202
references: Dis Esophagus. 2004;17(2):150-4
references: 15230729
references: Lung Cancer. 2010 May;68(2):154-60
references: 19628293
references: Lancet. 2012 Apr 28;379(9826):1602-12
references: 22440946
references: Gan. 1980 Apr;71(2):260-4
references: 7202921
references: Br J Cancer. 2008 Jun 3;98(11):1781-3
references: 18506182
references: Clin Cancer Res. 2002 Jan;8(1):202-9
references: 11801560
references: PLoS One. 2011;6(9):e24285
references: 21931671
references: Oncogene. 2009 May 14;28(19):2024-33
references: 19363520
references: J Pathol. 2002 Oct;198(2):142-56
references: 12237873
references: Clin Cancer Res. 2005 Nov 15;11(22):8213-21
references: 16299255
references: Cancer Prev Res (Phila). 2011 Nov;4(11):1728-35
references: 21778329
references: Mol Carcinog. 2010 Mar;49(3):235-46
references: 19908241
references: Clin Cancer Res. 2007 Jan 1;13(1):144-51
references: 17200349
references: J Pharm Pharmacol. 2003 Apr;55(4):519-26
references: 12803774
references: J Pharmacol Exp Ther. 1979 Jul;210(1):106-11
references: 448638
references: Int J Cancer. 2003 Dec 10;107(5):844-53
references: 14566837
references: Cancer Res. 1981 May;41(5):1954-7
references: 7214363
references: PLoS One. 2010 Sep 15;5(9):e12715
references: 20856806
references: Methods Mol Med. 2001;58:205-13
references: 21340860
references: Oncogene. 2010 Oct 7;29(40):5475-89
references: 20661220
references: Apoptosis. 2011 Sep;16(9):889-901
references: 21739277
references: Gynecol Oncol. 2009 Jul;114(1):3-11
references: 19410283
references: Eur J Pharmacol. 2011 Jan 10;650(1):170-7
references: 20969859
references: Lancet Oncol. 2009 May;10(5):501-7
references: 19410194
references: Mol Carcinog. 2007 Oct;46(10):857-64
references: 17415779
references: Breast Cancer Res Treat. 1986;8(3):249-55
references: 3593988
references: Int J Oncol. 2012 Feb;40(2):527-34
references: 21971589
references: Int J Cancer. 1990 Mar 15;45(3):416-22
references: 2307530
references: J Pathol. 2004 Jul;203(3):744-53
references: 15221933
references: J Clin Lab Immunol. 1983 Aug;11(4):181-7
references: 6321738
references: Cancer Sci. 2004 Nov;95(11):901-7
references: 15546508
references: Biochem Biophys Res Commun. 2001 Nov 2;288(3):579-85
references: 11676482
references: Int J Cancer. 2013 Feb 15;132(4):843-53
references: 22752934
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Cancer Lett. 2010 Apr 1;290(1):96-103
references: 19828235
references: Int J Gynecol Cancer. 2008 May-Jun;18(3):492-8
references: 17692085
references: Oncol Rep. 2008 Sep;20(3):605-11
references: 18695912
references: J Natl Cancer Inst. 2010 Jun 2;102(11):812-27
references: 20484106
references: Cancer Res. 2005 Sep 1;65(17):7911-6
references: 16140962