Antisense blocking of BRCA1 enhances sensitivity to plumbagin but not tamoxifen in BG-1 ovarian cancer cells.
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.
Srinivas
Gopal
G
Division of Cancer Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India.
Annab
Lois A
LA
Gopinath
Gokul
G
Banerji
Asoke
A
Srinivas
Priya
P
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019313:BRCA1 Protein / Q000037:antagonists & inhibitors*; D002455:Cell Division / Q000187:drug effects; D004642:Emodin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009285:Naphthoquinones / Q000627:therapeutic use*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016372:RNA, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D019313:BRCA1 Protein; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D009285:Naphthoquinones; D016372:RNA, Antisense; D012333:RNA, Messenger; D013629:Tamoxifen; D004642:Emodin; C014758:plumbagin