Abstract C234: A novel microtubule inhibitor BPR0L075 overcomes paclitaxel resistance in ovarian cancer cell lines

Abstract

Abstract Background: The therapy of choice for women with advanced ovarian cancer involves paclitaxel (Taxol®). However, patients develop resistance to paclitaxel during the course of treatment, which is associated with overexpression of P-glycoprotein and alterations involving class III beta-tubulin. BPR0L075 [6-methoxy-3-(3′,4′,5′-trimethoxy-benzoyl)-1H-indole] is a novel synthetic indole compound that inhibits tubulin polymerization through binding to the colchicines-binding site of tubulin (Kuo et al., Cancer Research , 2004). We investigated the activity of BPR0L075 in highly taxol resistant ovarian cancer cell lines. Methods: human ovarian cancer cell lines OVCAR-3, SKOV-3, and Taxol resistant subclones OVCAR-3/TR(0.5µM Taxol), SKOV-3/TR(0.25µM Taxol) were used for cytotoxicity and apoptosis evaluations. Results: BPR0L075 displays potent and broad-spectrum cytotoxic activities at low nanomolar concentrations against parental and drug resistant ovarian cancer cell lines investigated, regardless of the expression levels of the multidrug resistance ABC transporters P-gp and BCRP or class III beta-tubulin. Cell cycle analysis revealed the BPR0L075 induced G2/M cell cycle arrest. Furthermore, western blot analysis shows BPR0L075 treatment increases cyclin B1 levels, cleaves poly(ADP-ribose) polymerase, induces BCl-XL phosphorylation. BPR0L075 may induce apoptosis via a caspase-3 independent mechanism in ovarian cancer cell lines. Conclusion: The present study shows that BPR0L075 is active in drug resistant ovarian cancer cells, suggesting that BPR0L075 is a promising candidate for development as a novel microtubule therapeutic. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C234.