Browsing by Author "Somasundaram, V"

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    Increased sensitivity of BRCA defective triple negative breast tumors to plumbagin through induction of DNA Double Strand Breaks (DSB)
    (SCIENTIFIC REPORTS, 2016) Nair, RS; Kumar, JM; Jose, J; Somasundaram, V; Hemalatha, SK; Sengodan, SK; Nadhan, R; Anilkumar, TV; Srinivas, P
    We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ovarian cancer cells; however, the effect of this molecule in BRCA1 mutated breast cancers has not been analyzed yet. Here, we report that reactive oxygen species (ROS) induced by PB resulted in DNA DSB and activates downstream signaling by ATR/ATM kinases and subsequent apoptosis. PB reduces DNA-dependent protein kinase (DNA-PK) expression and inhibits NHEJ (Non Homologous End Joining) activity in BRCA1 defective breast cancer cells. Also, PB induces apoptosis in two different BRCA1 conditional knock out murine models: MMTV-Cre; BRCA1(Co/Co) and WAP-Cre; BRCA1(Co/Co), at 2 mg/kg body weight, but 32 mg/kg of carboplatin (CN) was needed to induce apoptosis in them. This is the first study where two different tissue specific promoter driven transgenic mice models with BRCA1 exon 11 deletions are used for preclinical drug testing. The apoptosis induced by PB in HR (Homologous Recombination) defective triple negative BRCA1 mutant cell lines and in mouse models occur by inducing ROS mediated DNA DSB. The toxicity profile as compared with CN in transgenic mice provides evidence for PB's safer disposition as a therapeutic lead in breast cancer drug development.
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    Structure activity relationship of plumbagin in BRCA1 related cancer cells
    (MOLECULAR CARCINOGENESIS, 2013) Thasni, KA; Ratheeshkumar, T; Rojini, G; Sivakumar, KC; Nair, RS; Srinivas, G; Banerji, A; Somasundaram, V; Srinivas, P
    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-m, suppression subtractive hybridization, microarray, molecular docking and estrogen receptorDNA 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 TRAILDR5 complexes to activate the extrinsic pathway of apoptosis. Since the antiproliferative activity of plumbagin could be reduced by inhibiting ER, we speculated that plumbagin interferes with the binding of ER 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. (c) 2012 Wiley Periodicals, Inc.