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.