Antisense blocking of BRCA1 enhances sensitivity to plumbagin but not tamoxifen in BG-1 ovarian cancer cells.

Abstract

Previous studies have shown that reduction in BRCA1 mRNA and protein can result in increased proliferation of BG-1 ovarian cancer cells in both in vitro and in vivo conditions, suggesting that BRCA1 may normally act as a growth inhibitor in these cells. Also, there are other reports that suggest that wild-type BRCA1 protein may repress estrogen receptor (ER) function either directly or indirectly. However, response to antiestrogen drugs in BRCA1-blocked ER-positive ovarian cancer cells has not been reported, and this served as the rationale for this study. We analyzed the effect of tamoxifen, emodin, and plumbagin in BRCA1-blocked ER-positive BG-1 ovarian cancer cells. For all three drugs, BRCA1-blocked cells were more sensitive than the corresponding control cells as assessed by MTT assay; however, only plumbagin showed a statistically significant difference in mean viability (P < 0.05). All three drugs induced loss of mitochondrial membrane potential (DeltaPsi(m)), nuclear condensation, DNA fragmentation, and morphological changes, as observed after 6 h of drug treatment, suggesting apoptosis induction in both BRCA1-blocked and control cells. However, apoptosis induction was greater in BRCA1-blocked cells, the efficacy being in the order of plumbagin > tamoxifen > emodin. The dose of plumbagin needed to kill 50% was 5 microM in the control cells and 2.68 microM for the BRCA1-blocked cells, indicating that the latter was about twofold more sensitive to plumbagin than the wild-type cells. This throws light on the fact that plumbagin may have chemotherapeutic potential as an anticancer agent in BRCA1-mutated ovarian cancer patients.

• Authors: Gopal Srinivas, Lois A Annab, Gokul Gopinath, Asoke Banerji, Priya Srinivas
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 39 Issue 1 Pg. 15-25 (Jan 2004) ISSN: 0899-1987 [Print] United States
• PMID: 14694444 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Antineoplastic Agents, Phytogenic
• BRCA1 Protein
• Enzyme Inhibitors
• Estrogen Antagonists
• Naphthoquinones
• RNA, Antisense
• RNA, Messenger
• Tamoxifen
• Emodin
• plumbagin

Topics

• Antineoplastic Agents, Phytogenic (therapeutic use)
• Apoptosis (drug effects)
• BRCA1 Protein (antagonists & inhibitors)
• Cell Division (drug effects)
• Emodin (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Estrogen Antagonists (therapeutic use)
• Female
• Humans
• In Situ Nick-End Labeling
• Membrane Potentials (drug effects)
• Mitochondria (drug effects, metabolism)
• Naphthoquinones (therapeutic use)
• Neoplasms, Hormone-Dependent (drug therapy, metabolism, pathology)
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• RNA, Antisense (pharmacology)
• RNA, Messenger (metabolism)
• Tamoxifen (therapeutic use)
• Tumor Cells, Cultured