BMC Cancer Research article Tamoxifen and the Rafoxifene analog LY117018: their effects on arachidonic acid release from cells in culture and on prostaglandin I2 production by rat liver cells Lawrence Levine* BioMed Central Open Access Address: Department of Biochemistry, Brandeis University Waltham, MA 02454, USA Email: Lawrence Levine* - llevine@brandeis.edu * Corresponding author Published: 13 August 2004 BMC Cancer 2004, 4:49 doi:10.1186/1471-2407-4-49 This article is available from: http://www.biomedcentral.com/1471-2407/4/49 Received: 01 March 2004 Accepted: 13 August 2004 © 2004 Levine; licensee BioMed Central Ltd. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Tamoxifen is being used successfully to treat breast cancer. However, tamoxifen also increases the risk of developing endometrial cancer in postmenopausal women. Raloxifene also decreases breast cancer in women at high risk and may have a lower risk at developing cancer of the uterus. Tamoxifen has been shown to stimulate arachidonic acid release from rat liver cells. I have postulated that arachidonic acid release from cells may be associated with cancer chemoprevention. Methods: Rat liver, rat glial, human colon carcinoma and human breast carcinoma cells were labelled with [3H] arachidonic acid. The release of the radiolabel from these cells during incubation with tamoxifen and the raloxifene analog LY117018 was measured. The prostaglandin I2 produced during incubation of the rat liver cells with µM concentrations of tamoxifen and the raloxifene analog was quantitatively estimated. Results: Tamoxifen is about 5 times more effective than LY117018 at releasing arachidonic acid from all the cells tested. In rat liver cells only tamoxifen stimulates basal prostaglandin I2 production and that induced by lactacystin and 12-O-tetradecanoyl-phorbol-13-acetate. LY117018, however, blocks the tamoxifen stimulated prostaglandin production. The stimulated prostaglandin I2 production is rapid and not affected either by preincubation of the cells with actinomycin or by incubation with the estrogen antagonist ICI-182,780. Conclusions: Tamoxifen and the raloxifene analog, LY117018, may prevent estrogen-independent as well as estrogen-dependent breast cancer by stimulating phospholipase activity and initiating arachidonic acid release. The release of arachidonic acid and/or molecular reactions that accompany that release may initiate pathways that prevent tumor growth. Oxygenation of the intracellularly released arachidonic acid and its metabolic products may mediate some of the pharmacological actions of tamoxifen and raloxifene. Background The successful treatment and prevention of estrogen- dependent breast cancer in women by tamoxifen is attrib- uted to its estrogen receptor (ER) occupancy [reviewed in [1,2]]. In the N-nitrosomethylurea (NMU) induced breast cancer model in rats, tumor growth is estrogen dependent Page 1 of 8 (page number not for citation purposes)