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Plumbagin (5-hydroxy 2-methyl 1, 4-naphthaquinone), isolated from Plumbago zeylanica, is an agent that has broad spectrum antitumor activity. At RGCB, we had observed plumbagin has an increased propensity for apoptosis in BRCA1-blocked cells (BG1, ovarian cancer cells) than BRCA1-unblocked cells. Also, plumbagin has been shown to have anti-cancer activity not only in BRCA1-defective tumor but also in various other cancer cells. Plumbagin may become a promising anti-cancer molecule because it acts via the generation of reactive oxygen species (ROS) that can create DNA damage and increase the incidence of cell death. The N-terminal region of BRCA1 is of critical importance in binding to the estrogen receptor. Using a cell system where the N-terminal region of BRCA1 was lacking, we have shown that plumbagin inhibits the ER signaling pathway by causing an upregulation in the expression of 46 kDa isoform of ER?, which is reported to causes inhibition of the hER66-kDa mediated transactivation and thus inhibits estrogen-mediated cell growth. Plumbagin affects cells in a number of processes that involve the BRCA1 protein in the normal intracellular scenario. BRCA1 maintains genomic integrity and helps in the repair of DNA breaks. Plumbagin on the other hand causes genotoxicity. BRCA1, being a tumor suppressor gene controls cell growth by inhibition of topoisomerase II, tubulin polymerization, VEGF, and inhibition of ER?. Plumbagin also is reported to have similar functions with respect to ROS-mediated inhibition of topoisomerase II and inhibition of tubulin polymerization BRCA1 downregulates ROS generation, while plumbagin induces ROS-mediated damages. Thus, plumbagin would be an ideal anti-cancer compound to target BRCA1-defective tumors as it would be able to mitigate the deleterious effects caused by the presence of a defective BRCA1 protein or the total absence of BRCA1 and thus also prevent malignant transformation. We have also reported that plumbagin is nontoxic to HBL 100 cells in comparison with HeLa, in which it can induce apoptosis at an even lower concentration. Plumbagin's toxic side effects include diarrhea, skin rashes, and hepatic and reproductive toxicity but plumbagin has been reported to be non toxic at doses shown to elicit chemopreventive and therapeutic effects and at least 8 times higher doses are required to elicit the toxic side effects. Plumbagin thus has the potential to act as an anti-cancer agent with commendable specificity toward cancerous cells.
ANNEXIN PI Staining
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ER a expression by western blot in AS4 and NEO cells
Plumbagin activate death receptor mediated pathway
In silico analysis of plumbagin with death receptors
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RGCB