Abstract #2818: Growth inhibition of human breast cancer cells with an iron chelator and a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor

Cell treatment with iron chelators results in G₁/S arrest and apoptosis. Tumor cells appear to be more sensitive to iron chelation probably because they express higher levels of the iron containing enzyme, ribonucleotide reductase. Previously our laboratory has shown that an iron chelator inhibited the growth of a variety of cancer cell lines and also prolonged survival in tumor bearing mice. The mammalian target of rapamycin, mTOR, is a member of the phosphatidylinositol 3-kinase (PI3-K) /Akt family and plays a key role in cell growth and survival. The PI3-K/mTOR pathway is often constitutively activated in human tumor cells. BEZ235 (Novartis Pharma AG) is a potent, oral, dual PI3-K/mTOR inhibitor currently in Phase I clinical trials. The purpose of this study was to assess the in vitro effects of combining an iron chelator (Exjade: Novartis Pharma AG) and BEZ235 on the growth of MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells. Cells were exposed to Exjade (0.5 - 5 \#956;M) or BEZ235 (1.5-6 nM) alone or in combination for 3 days (9 different dose combinations were tested). Cell growth was determined using the colorimetric MTT tetrazolium dye assay. The Chou-Talalay method of isobologram analysis was performed to determine the inhibitory effect. Dose-dependent growth inhibition was observed in both the MCF-7 and the HER-2/neu-tranfected MCF-7 cells after 3 days exposure to Exjade (IC50: 1.5 \#956;M and 2.3 \#956;M, respectively) or BEZ235 (IC50: 5.0 nM and 3.7 nM, respectively). Exposure to the combination of Exjade and BEZ235 resulted in additive growth inhibition in both the MCF-7 and HER-2/neu-transfected MCF-7 human breast cancer cells. Sequencing experiments showed that exposing the MCF-7 cells to Exjade 6 hours prior to exposure to BEZ235 gave similar inhibitory effects as simultaneous addition. Treatment of cells with BEZ235 6 hours prior to Exjade, however, resulted in loss of the additive inhibitory effect, with inhibition being no better than that seen with either agent alone. These results suggest this combination warrants further investigation as a therapeutic strategy for breast cancer.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2818.