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

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 19; pp. 4735 - 4742
• Main Authors: Amrutha, K., Nanjan, Pandurangan, Shaji, Sanu K., Sunilkumar, Damu, Subhalakshmi, K., Rajakrishna, Lakshmi, Banerji, Asoke
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-10-2014
• Subjects: Apoptosis - drug effects; Breast cancer; Cell Cycle - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Chrysoeriol; COX-2; Dose-Response Relationship, Drug; Drug Discovery; Flavones - chemical synthesis; Flavones - chemistry; Flavones - pharmacology; Humans; Metastasis; Methylated flavonoids; Molecular Structure; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB; Signal Transduction - drug effects; Structure-Activity Relationship; NF-κB; Chrysoeriol; Breast cancer; Metastasis; COX-2; Methylated flavonoids
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.07.093

Summary of the molecular (expression of MMP-9 and COX-2, and activation of NF-κB), and cellular effects (migration, invasion and cell cycle) of chrysoeriol. The black arrows indicate induction, and the grey lines indicate inhibition. The thickness of the arrows corresponds to the level of induction by PMA or doxorubicin. The numbers in the grey boxes denotes the fold induction (+), or inhibition (−).
Seventeen flavonoids with different substitutions were evaluated for inhibition of nuclear factor-κB (NF-κB) signaling in the invasive breast cancer cell line MDA-MB-231. They were screened using an engineered MDA-MB-231 cell line reporting NF-κB activation. The modulation of expression of two NF-κB 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-κB, 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-κB signaling inhibitors was studied. The study indicates differences between the actions of various flavonoids on NF-κB activation and on the biological activities of breast cancer cells. Flavones in general, were more active than the corresponding flavonols.