Furanoflavones pongapin and lanceolatin B blocks the cell cycle and induce senescence in CYP1A1-overexpressing breast cancer cells

摘要: Abstract Expression of cytochrome P450-1A1 (CYP1A1) is suppressed under physiologic conditions but induced (a) by polycyclic aromatic hydrocarbons (PAHs) which can be metabolized CYP1A1 to carcinogens, and (b) in majority breast cancers. Hence, phytochemicals or dietary flavonoids, if identified as inhibitors, may help preventing PAH-mediated carcinogenesis cancer. Herein, we have investigated the cancer chemopreventive potential a flavonoid-rich Indian medicinal plant, Pongamia pinnata (L.) Pierre. Methanolic extract its seeds inhibits CYP1A1-overexpressing normal human HEK293 cells, with IC50 0.6 µg/mL. Its secondary metabolites, furanoflavonoids pongapin/lanceolatin B, inhibit 20 nM. Although furanochalcone pongamol only 4.4 µM, semisynthetic pyrazole-derivative P5b, has ∼10-fold improved potency (IC50, 0.49 μM). Pongapin/lanceolatin B methanolic P. protect cells from B[a]P-mediated toxicity. Remarkably, they also block cell cycle MCF-7 at G0-G1 phase, repress cyclin D1 levels induce cellular-senescence. Molecular modeling studies demonstrate interaction pattern CYP1A1. The results strongly indicate seed-extract for further development agents.