Abstract
Paclitaxel plays a major role in the treatment of ovarian cancer; however, resistance to paclitaxel is frequently observed. Thus, new therapy that can overcome paclitaxel resistance will be of significant clinical importance. We evaluated antiproliferative effects of an antimitotic and antivascular 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 induces cell death by a dual mechanism in parental and paclitaxel-resistant ovarian cancer cells. In the parental cells (OVCAR-3 and SKOV-3), BPR0L075 induced apoptosis, evidenced by poly(ADP-ribose) polymerase (PARP) cleavage and DNA ladder formation. 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. Immunoblotting analysis shows that BPR0L075 treatment induced up-regulation of cyclin B1, BubR1, MPM-2, and survivin protein levels and Bcl-XL phosphorylation in parental cells; however, in resistant cells, the endogenous expressions of BubR1 and survivin were depleted, BPR0L075 treatment failed to induce MPM-2 expression and phosphorylation of Bcl-XL. BPR0L075 induced cell death in both parental and paclitaxel-resistant ovarian cancer cells proceed through caspase-3 independent mechanisms. 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 novel microtubule therapeutic to overcome multidrug resistance and trigger alternative cell death by mitotic catastrophe in ovarian cancer cells that are apoptosis-resistant.
Highlights
Ovarian cancer, the most lethal malignancy of the gynecologic cancer, results annually in over 14,000 U.S and 114,000 worldwide deaths
We tested the cytotoxicity of BPR0L075 in human ovarian cancer cell lines SKOV-3, OVCAR-3, and A2780-1A9 as well as the paclitaxel-resistant sublines SKOV-3-TR, OVCAR-3-TR, and 1A9-PTX10, which were selected under continuous exposure of 0.25 mM paclitaxel (SKOV-3-TR), 0.5 mM paclitaxel (OVCAR-3-TR), and 15 ng/mL paclitaxel and 5 mg/mL verapamil (1A9-PTX10), respectively
The results show that efflux transporter P-gp contributed to the selected paclitaxel resistance in SKOV-3TR and OVCAR-3-TR cells, but BPR0L075 is not a substrate for efflux pumps, which contributes to its ability to overcome paclitaxel resistance
Summary
The most lethal malignancy of the gynecologic cancer, results annually in over 14,000 U.S and 114,000 worldwide deaths. Despite advances in the diagnosis and treatment, the five-year survival rate for stage IV patients is about 18% [1,2]. The inability to overcome drug resistance and inhibit metastasis represents the major cause of treatment failure [3]. Innovative and effective new therapeutics that overcome drug resistance are critically needed to improve the survival and quality of life of patients with this disease. For paclitaxel, despite significant initial response for advanced ovarian cancer using paclitaxel and cisplatin based combination therapy, the vast majority of patients relapse and develop drug-resistance [5,6]. The identification of novel antimitotic agent that can overcome taxane resistance, display endurable activity in taxanerefractory tumors could potentially bring clinical benefits to patients with advanced ovarian cancer
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