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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.

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


Authors

Rajni Sharma

Ibidapo Williams Ibidapo.Williams@uwe.ac.uk
Research Fellow- Cell Cultural Monitoring Technology

Gatchie Linda

Vinay R. Sonawane

Bhabatosh Chaudhuri

Sandip B. Bharate



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.

Citation

Sharma, R., Williams, I. S., Linda, G., Sonawane, V. R., Chaudhuri, B., & Bharate, S. B. (2018). Furanoflavones pongapin and lanceolatin B blocks the cell cycle and induce senescence in CYP1A1-overexpressing breast cancer cells. Bioorganic and Medicinal Chemistry, 26(23-24), 6076-6086. https://doi.org/10.1016/j.bmc.2018.11.013

Journal Article Type Article
Acceptance Date Nov 9, 2018
Online Publication Date Nov 10, 2018
Publication Date Dec 15, 2018
Publicly Available Date Nov 11, 2019
Journal Bioorganic and Medicinal Chemistry
Print ISSN 0968-0896
Electronic ISSN 1464-3391
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.

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