Sequential treatment with Antimitotic Drugs and a Bcl-xL Inhibitor Induces Mitotic Cell Death

Abstract

The cell cycle is regulated by checkpoints that ensure proper chromosome segregation, with the spindle assembly checkpoint (SAC) playing a central role during mitosis. Microtubule-targeting agents such as Paclitaxel and Epothilone B disrupt spindle dynamics and activate the SAC, inducing mitotic arrest. However, resistant cancer cells exit mitotic arrest through mitotic slippage leading to a possible relapse, limiting therapeutic efficacy. While combining mitotic inhibitors with antiapoptotic protein inhibition can overcome resistance, such strategies are associated with high toxicity, and most in vitro studies employ prolonged drug exposure, which is not feasible in vivo due to rapid blood clearance. This study demonstrated that short-term treatment with Epothilone B and Paclitaxel induced prolonged abnormal mitotic outcomes even after drug washout, highlighting a new window of vulnerability in resistant cell lines. Additionally, sequential treatment with a Bcl-xL inhibitor, even up to 3 days after washout, significantly enhanced cell death, offering promising clinical implications with minimized toxicity.