期刊
BIOCHIMIE
卷 105, 期 -, 页码 36-44出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2014.06.002
关键词
Lemons; Obacunone glucoside; Aromatase; Breast cancer; Anti-inflammation; Stability
资金
- USDA-NIFA Designing Foods for Health, through the Vegetable & Fruit Improvement Center [2010-34402-20875]
Overexpression of the aromatase enzyme CYP19 has been implicated in the onset of estrogen-dependent breast carcinogenesis. Obacunone, a natural compound present in citrus fruits, has been demonstrated for various biological activities including anti-cancer and anti-inflammatory properties. In the present study, we have isolated obacunone and obacunone glucoside (OG) from lemon seeds, then fractionated these compounds using chromatographic techniques and characterized them by HPLC, LC-MS, and 2D NMR spectral analysis. To investigate the mechanism of anti-cancer and anti-aromatase activities of limonoids, their cytotoxic effect was tested on human breast cancer (MCF-7) and non-malignant (MCF-12F) breast cells. MTT assays confirmed that obacunone was strongly inhibited MCF-7 cell proliferation without affecting non-malignant breast cells. Treatment with obacunone increased apoptosis by up-regulating expression of the pro-apoptotic protein Bax and down-regulating the anti-apoptotic protein BcI2, as well as inducing G1 cell cycle arrest. In addition, obacunone significantly inhibited aromatase activity in an in vitro enzyme assay. Exposure of MCF-7 breast cancer cells to obacunone down-regulated expression of inflammatory molecules including nuclear factor-kappa B (NF-kappa B) and cyclooxygenase-2 (COX-2). Furthermore, we found that obacunone inhibited COX-2 and NF-kappa B by activation of the p38 mitogen-activated protein kinase (MAPK). Finally, the uptake level of obacunone into MCF-7 cells was measured by HPLC and its structure was confirmed by LC-HR-MS. This study demonstrated that obacunone may have the potential to prevent estrogen-responsive breast cancer through inhibition of the aromatase enzyme and inflammatory pathways, as well as activation of apoptosis. (C) 2014 Elsevier Masson SAS. All rights reserved.
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