Discovery of lesser known flavones as inhibitors of NF-κB signaling in MDA-MB-231 breast cancer cells-A SAR study

Seventeen flavonoids with different substitutions were evaluated for inhibition of nuclear factor-kappa B (NF-kappa B) signaling in the invasive breast cancer cell line MDA-MB-231. They were screened using an engineered MDA-MB-231 cell line reporting NF-kappa B activation. The modulation of expression of two NF-kappa B regulated genes involved in tumorigenesis, matrix metalloproteinase-9 (MMP-9), and cyclooxygenase-2 (COX-2) were also analyzed in these cells. Among the compounds tested, all except gossypetin and quercetagetin inhibited the activation of NF-kappa B, and the expression of MMP-9 and COX-2 to different degree. Methylated flavone, chrysoeriol (luteolin-3'-methylether), was found to be the most potent inhibitor of MMP-9 and COX-2 expressions. The effect of chrysoeriol on cell proliferation, cell cycle, apoptosis and metastasis was analyzed by established methods. Chrysoeriol caused cell cycle arrest at G2/M and inhibited migration and invasion of MDA-MB-231 cells. The structure-activity relations amongst the flavonoids as NF-kappa B signaling inhibitors was studied. The study indicates differences between the actions of various flavonoids on NF-kappa B activation and on the biological activities of breast cancer cells. Flavones in general, were more active than the corresponding flavonols. (C) 2014 Elsevier Ltd. All rights reserved.