title: Structure activity relationship of plumbagin in BRCA1 related cancer cells.
abstract: It has been shown earlier that plumbagin, a naturally occurring naphthaquinone has specific anticancer activity in BRCA1 blocked ovarian cancer cells. Plumbagin can induce estrogen dependent cell signaling and apoptosis in BRCA1 blocked ovarian cancer cells. Being a reactive oxygen species (ROS) generator and apoptosis inducing agent, plumbagin has immense potential as a promising anticancer agent. In this study we analyzed whether there would be increased anticancer activity if the positions of the functional groups on plumbagin were altered and further to analyze the detailed molecular mechanism of action of the lead molecule. Methods like MTT assay, apoptosis analysis by flow cytometry, assessment of mitochondrial membrane potential-Δψm , suppression subtractive hybridization, microarray, molecular docking and estrogen receptor-DNA binding activity by electrophoresis mobility shift assay (EMSA) were adopted for assessing the anticancer activity. Consequently we found that, plumbagin was the most potent anticancer agent when compared to structurally related compounds. The anti-cancer activities were in the order plumbagin > 1,4-naphthaquinone > juglone > lawsone > menadione. Molecular docking studies showed that plumbagin could be well docked in the receptor ligand complex of TRAIL-DR5 complexes to activate the extrinsic pathway of apoptosis. Since the antiproliferative activity of plumbagin could be reduced by inhibiting ERα, we speculated that plumbagin interferes with the binding of ERα to ERE and we confirmed this by EMSA. This study clearly indicates that plumbagin can induce multiple pathways of apoptosis and cell cycle arrest in BRCA1 blocked cells compared to unblocked cells.
authors.affiliation: Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
authors.forename: Thasni
authors.initials: T
authors.lastname: K A
authors.forename: Ratheeshkumar
authors.initials: R
authors.lastname: T
authors.forename: Rojini
authors.initials: R
authors.lastname: G
authors.forename: Sivakumar
authors.initials: S
authors.lastname: K C
authors.forename: Rakesh Sathish
authors.initials: RS
authors.lastname: Nair
authors.forename: Srinivas
authors.initials: S
authors.lastname: G
authors.forename: Asoke
authors.initials: A
authors.lastname: Banerji
authors.forename: Veena
authors.initials: V
authors.lastname: Somasundaram
authors.forename: Priya
authors.initials: P
authors.lastname: Srinivas
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D062105:Molecular Docking Simulation; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D013329:Structure-Activity Relationship; D059467:Transcriptome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D047628:Estrogen Receptor alpha; D009285:Naphthoquinones; D011065:Poly(ADP-ribose) Polymerases; C035342:1,4-naphthoquinone; C005134:juglone; C014758:plumbagin