Furanoflavones pongapin and lanceolatin B blocks the cell cycle and induce senescence in CYP1A1-overexpressing breast cancer cells
Authors: Bhabatosh Chaudhuri
Vinay R Sonawane
Ibidapo S Williams
Sandip B Bharate
Rajni Sharma
Linda Gatchie
Journal: Bioorganic & Medicinal Chemistry (2018)
Discipline: CHEMISTRY
Keywords: CYP1A1; Cell cycle; Furanoflavones; Lanceolatin B; Pongapin
Affiliations: Natural Products Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India., CYP Design Ltd, The Innovation Centre, 49 Oxford Street, Leicester LE1 5XY, UK., CYP Design Ltd, The Innovation Centre, 49 Oxford Street, Leicester LE1 5XY, UK; Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK. Electronic address: ., Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: .

Abstract:  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. 

Retracted: No

PubPeer comments:
 Would the authors be able to post the uncropped blot supporting figure 4G? *** Inverse image ![file] *** ![file] , 
 #1 Dear Pupbeer, I understand your concern over the western blot picture in this paper. Unfortunately, the original western blot data is in the university (DMU Leicester). The corresponding author Professor Bhabatosh Chaudhuri has untimely retired due to his health deterioration. Thus, the data cannot be accessed anymore. All data I have with me is the data that I generated at the time of the experiment which is placed in a PowerPoint file. I assure you that the data presented in the manuscript is completely original. As a lead biology author, I state that the data and results presented are true output of the actually done Western-blot experiment. I hope this would satisfy your query. Best wishes, Ibidapo , 
 The comments pertaining to this publication are related to the biological experiments (Western-blots) which were conducted by authors, Ibidapo S. Williams, Linda Gatchie, Vinay R. Sonawane, and mentored by Prof. Bhabatosh Chaudhuri at CYP Design Ltd, UK. My group performed natural products isolation, synthesis (Fig. 1, Fig. 2), and molecular modeling (Fig. 5) in this paper. These compounds were provided to Prof. Bhabatosh Chaudhuriu2019s group for biological investigations. Thus, there are no clarifications against these comments from my side. At my end, these authors have been contacted via email. One of the biology authors, Ibidapo S. Williams has already responded at this forum. Further clarifications (if any) will be provided by the biology authors mentioned above. ,