期刊
MOLECULAR CARCINOGENESIS
卷 52, 期 5, 页码 392-403出版社
WILEY-BLACKWELL
DOI: 10.1002/mc.21877
关键词
quinones; plumbagin; BRCA1; suppression subtractive hybridization; microarray
资金
- Kerala State Council for Science Technology and Environment [[T] 28/SRS/2005/CSTE]
- Department of Science and Technology (DST) [SR/FT/L-111/2003]
- Council for Scientific and Industrial Research, Government of India
- Department of Atomic Energy, Government of India
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.
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