Abstract
Abstract Paclitaxel resistance is a significant clinical problem. In the current study, we evaluated antiproliferative effects of a tubulin binding agent BPR0L075 in paclitaxel-resistant ovarian cancer cells. BPR0L075 displays potent and broad-spectrum cytotoxicity at low nanomolar concentrations (IC50 = 2-7 nM) against both parental ovarian cancer cells (OVCAR-3, SKOV-3, and A2780-1A9) and paclitaxel-resistant sublines (OVCAR-3-TR, SKOV-3-TR, 1A9-PTX10), regardless of the expression levels of the multidrug resistance transporter P-gp and class III β-tubulin or mutation of β-tubulin. BPR0L075 blocks cell cycle at the G2/M phase in paclitaxel-resistant cells while equal concentration of paclitaxel treatment was ineffective. BPR0L075 induced cell death in paclitaxel-resistant ovarian cancer cells (OVCAR-3-TR and SKOV-3-TR) is primarily due to mitotic catastrophe, evidenced by formation of giant, multinucleated cells and absence of PARP cleavage and DNA fragmentation. Immunoblot analysis shows that survivin protein expression was depleted in resistant cells. BPR0L075 induced cell death in the paclitaxel-resistant ovarian cancer cells proceed through caspase-3 independent mechanisms, supported by the absence of caspase-3 cleavage and ineffectiveness of caspase-3 inhibitor in protecting the resistant cells from BPR0L075 induced cell death. In conclusion, BPR0L075 displays potent cytotoxic effects in ovarian cancer cells with a potential to overcome paclitaxel resistance by bypassing efflux transporters and inducing mitotic catastrophe. BPR0L075 represents a promising antimitotic agent in controlling taxane-resistant ovarian cancer cells. Citation Format: Xinli Liu, Weimin Sun, Xiaolei Wang, Erxi Wu. Tubulin binding agent BPR0L075 induces iitotic catastrophe in paclitaxel-resistant ovarian cancer cells that is independent of caspase-3 activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4500. doi:10.1158/1538-7445.AM2013-4500
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