The In vitro effects of mevastatin, fenretinide and geldanamycin on MCF -7 breast cancer cell growth

Abstract

BACKGROUND: Cancer cells usually show signs of elevated levels of HMG-CoA reductase to satisfy their increased need for lipids and isoprenoids, making them more sensitive than normal cells to the isoprenoid-depleting effects of statins. Mevastatin, a cholesterol-lowering drug belonging to the statins class, has been shown to arrest growth of HCTll6 colon cancer cells. Fenretinide, a vitamin A analogue, is a synthetic retinoid that is used in clinical trials for the treatment of several malignancies. Geldanamycin, a benzoquinoid antibiotic that has potent antiproliferative and antitumor effects, diminishes p185c-erbB2 protein tyrosine kinase in breast carcinoma cells by interacting with HSP90 which leads to the disintegration and destabilization the Rafl-HSP90 complex. PURPOSE: The aim of this study was to investigate the in vitro effects of mevastatin, fenretinide and geldanamycin, both individually and in combination, in a dose- and timedependent manner, on growth and apoptosis of the human breast cancer cell line, MCF-7. METHODS: Cell growth assays were used to monitor the growth of MCF-7 cells over a period of 5 days and a growth curve was obtained. Mevastatin, fenretinide and geldanamycin were evaluated for their antiproliferative and apoptotic effects on MCF-7 cells, using MTS assays and the Annexin- VCY3 Apoptosis Detection Kit. The combination effects of mevastatin and fenretinide on MCF-7 cell proliferation were also evaluated. Due to time constraints geldanamycin was not used in combination experiments. RESULTS: Exposure of MCF-7 cells to various concentrations of mevastatin for 24 hours produced a significant growth-limiting effect. Inhibition of MCF-7 cell growth upon treatment with mevastatin for 48 and 72 hours, showed no significant arrest of growth. After 48 hours incubation with fenretinide, MCF-7 cell growth was inhibited, but the same effect could not be demonstrated following 24 and 72 hours exposure to the retinoid. MCF-7 cells were also exposed to mevastatin, fenretinide and geldanamycin, both individually and in combination, and apoptosis was detected by fluorescence microscopy.