Multifaceted approach with a single drug for brca1 defective cancers
Priya Srinivas
Integrated Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thycaud PO, Thiruvananthapuram 695 014, Kerala, India
Abstract:
BRCA1 germ line mutations have been identified in nearly 50% of hereditary breast cancers and approximately 80% of cases with both hereditary breast and ovarian cancers. However, decreased BRCA1 expression due to hypermethylation of the BRCA1 promoter or loss of BRCA1 allele has been observed in 30-40% of sporadic breast cancers. Thus, BRCA1 may generally play a role in breast cancer development. BRCA1 maintains genomic integrity and helps in the repair of DNA double strand breaks and Homologous recombination. BRCA1, being a tumor suppressor gene controls cell growth by inhibition of topoisomerase II, ER, VEGF and ubiquitinating tubulin polymerization. BRCA1 also reported to down regulate cellular levels of ROS. BRCA1’s down regulation on p300 helps to prevent ER mediated cell proliferation. If these functions could be targeted together, we could specifically destroy the BRCA1 defective cancer cells. Plumbagin, a naphthaquinone is one such compound which is reported to cause genotoxicity by ROS mediated DNA damage, inhibition of topoisomerase II and inhibition of tubulin polymerization. Further, we proved that plumbagin could inhibit the classical ER mediated cell growth signaling. Our resarch have proved that Plumabgin could specifically inhibit growth of BRCA1 defective cancer cells.
