Abstract 2151: Evaluation of a citrus flavonoid as a chemopreventive agent against breast cancer

Abstract

Abstract Naringenin is a flavonone found in citrus fruits and tomatoes that may have anti-tumor properties. Previously, our lab discovered that naringenin induced the activity of AMP-activated protein kinase (AMPK) and reduced phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4EBP) in MCF-7 human breast cancer cells. These properties have been linked with anti-tumor actions of drugs such as metformin and mTOR inhibitors. Based on these findings, we tested the ability of naringenin (0 uM - 200 uM) to modulate growth of MCF-7 human breast cancer cells and E0771 murine mammary tumor cells. In both models for cancer cell growth, naringenin dose-dependently decreased live cell number in a time-dependent manner. Furthermore, results of flow cytometry and propidium iodide staining assays showed accumulation of apoptotic cells after naringenin treatment. Naringenin also decreased expression of cyclin D1 and elevated expression of pro-apoptotic protein Bax suggesting that naringenin may inhibit the proliferation of mammary tumor cells by inducing cell cycle arrest and promoting apoptosis. To test for dose-dependent accumulation of naringenin in mammary gland tissue, female mice were fed varying doses of naringenin (control, 0%; low dose,1.0 wt%; or high dose, 3.0 wt% naringenin) in a high saturated fat diet for 11 weeks. Body weights and cumulative food intake were not different between diet groups. Dietary naringenin resulted in dose-responsive accumulation in mammary gland. Relative accumulation of naringenin in tissues was greatest in liver (low dose, 7.61 ± 1.14 umol/kg tissue and high dose, 37.04 ± 8.33 umol/kg tissue) followed by mammary gland and muscle which had a similar magnitude of naringenin accumulation (low dose ∼ 0.4 umol/kg tissue and high dose naringenin, 2.5 umol/kg tissue) of accumulation. Naringenin and monoglucuronide naringenin were two of the main forms of accumulated flavonoid in mammary gland raising the possibility that naringenin and/or metabolites are the active form of flavonoid responsible for anti-tumor activity against mammary cancer. Evaluating the species of naringenin metabolites in mammary gland that exert pro-apoptotic actions will be important to evaluate in order to understand the potential of naringenin-rich foods to contribute to prevention of breast cancer in women. Citation Format: Jia-Yu Ke, Min Tian, Kara L. Kliewer, Steve J. Schwartz, Ken M. Reidl, Shin-yu Tsai, Lisa D. Yee, Martha A. Belury. Evaluation of a citrus flavonoid as a chemopreventive agent against breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2151. doi:10.1158/1538-7445.AM2014-2151