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Annals of Oncology Advance Access originally published online on January 10, 2008
Annals of Oncology 2008 19(4):696-705; doi:10.1093/annonc/mdm557
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

gynecologic tumors

Estrogen-dependent cell signaling and apoptosis in BRCA1-blocked BG1 ovarian cancer cells in response to plumbagin and other chemotherapeutic agents

K. A. Thasni1, S. Rakesh1, G. Rojini1, T. Ratheeshkumar1, G. Srinivas2 and S. Priya1,*

1 Laboratory of Molecular Therapeutics, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Thiruvananthapuram, Kerala
2 Department of Biochemistry, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, Kerala, India

* Correspondence to: Dr S. Priya, Division of Cancer Biology, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Thiruvananthapuram 695 014, Kerala, India. Tel: +91-471-2347975; Fax: +91-471-2348096; E-mail: priyasrinivas2000{at}yahoo.com

Background: Cellular response to chemotherapeutic drugs in the absence of BRCA1 either completely or partially had drawn less attention. The present study evaluated whether there is a differential inhibition of cell growth by selected compounds with respect to BRCA1 status in estrogen receptor (ER)-positive ovarian cancer cells.

Materials and methods: The BG1 ovarian cancer cells used in the experiments were antisensely blocked with BRCA1 gene. Growth inhibition and apoptotic induction were analyzed to evaluate the cytotoxic effects. Small interfering RNA (SiRNA) transfection, western blot analysis, RT–PCR analysis and molecular modeling were carried out to analyze the estrogen-dependent action of plumbagin.

Results: Although we found that all the compounds studied induce apoptosis, the induction was in the order of plumbagin > doxorubicin > tamoxifen > cisplatin. Plumbagin can bind to the active site of ER-{alpha}. Plumbagin, however, induced ER-{alpha} 46 kDa truncated isoform, which was found abundantly preempted in the cytoplasm compared with a 66-kDa full-length isoform. The truncated isoform is known to inhibit classical ER-{alpha} signaling pathways. SiRNA-transfected cells for ER-{alpha} exhibited lower cytotoxicity upon plumbagin treatment than the control-transfected cells.

Conclusion: Taken together, this study indicates that plumbagin has chemotherapeutic potential in BRCA1-mutated/defective ER-positive cancers.

Key words: BRCA1, cisplatin, doxorubicin, plumbagin, tamoxifen

Received for publication April 17, 2007. Revision received September 19, 2007. Revision received November 6, 2007. Accepted for publication November 7, 2007.


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