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

Sharma, Rajni; Williams, Ibidapo S; Linda, Gatchie; Sonawane, Vinay R.; Chaudhuri, Bhabatosh; Bharate, Sandip B.

Abstract

© 2018 Elsevier Ltd Expression of cytochrome P450-1A1 (CYP1A1) is suppressed under physiologic conditions but is induced (a) by polycyclic aromatic hydrocarbons (PAHs) which can be metabolized by CYP1A1 to carcinogens, and (b) in majority of breast cancers. Hence, phytochemicals or dietary flavonoids, if identified as CYP1A1 inhibitors, may help in preventing PAH-mediated carcinogenesis and breast cancer. Herein, we have investigated the cancer chemopreventive potential of a flavonoid-rich Indian medicinal plant, Pongamia pinnata (L.) Pierre. Methanolic extract of its seeds inhibits CYP1A1 in CYP1A1-overexpressing normal human HEK293 cells, with IC50 of 0.6 µg/mL. Its secondary metabolites, the furanoflavonoids pongapin/lanceolatin B, inhibit CYP1A1 with IC50 of 20 nM. Although the furanochalcone pongamol inhibits CYP1A1 with IC50 of only 4.4 µM, a semisynthetic pyrazole-derivative P5b, has ∼10-fold improved potency (IC50, 0.49 μM). Pongapin/lanceolatin B and the methanolic extract of P. pinnata seeds protect CYP1A1-overexpressing HEK293 cells from B[a]P-mediated toxicity. Remarkably, they also block the cell cycle of CYP1A1-overexpressing MCF-7 breast cancer cells, at the G0-G1 phase, repress cyclin D1 levels and induce cellular-senescence. Molecular modeling studies demonstrate the interaction pattern of pongapin/lanceolatin B with CYP1A1. The results strongly indicate the potential of methanolic seed-extract and pongapin/lanceolatin B for further development as cancer chemopreventive agents.

• Journal Article Type: Article
• Acceptance Date: Nov 9, 2018
• Online Publication Date: Nov 10, 2018
• Publication Date: Dec 15, 2018
• Deposit Date: Nov 13, 2018
• Publicly Available Date: Nov 11, 2019
• Journal: Bioorganic and Medicinal Chemistry
• Print ISSN: 0968-0896
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Issue: 23-24
• Pages: 6076-6086
• DOI: https://doi.org/10.1016/j.bmc.2018.11.013
• Keywords: furanoflavones, pongapin, lanceolatin B, cell cycle, senescence,; CYP1A1
• Public URL: https://uwe-repository.worktribe.com/output/855901
• Publisher URL: https://doi.org/10.1016/j.bmc.2018.11.013
• Related Public URLs: https://www.sciencedirect.com/science/article/pii/S0968089618316663?via%3Dihub
• Additional Information: Additional Information : This is the author's accepted manuscript. The final published version is available here: https://doi.org/10.1016/j.bmc.2018.11.013.
• Contract Date: Nov 13, 2018