Agents that target the mitotic spindle to disrupt cell division, such as taxanes and vinca-alkaloids, are widely used as anticancer drugs. As these drugs target microtubules, which have a wide variety of functions in non-mitotic cells, they also have a number of side effects. Weikang Tao and colleagues have investigated another component of the mitotic spindle, the KSP motor protein, which only functions during mitosis, and showed that KSP inhibitors have a unique mechanism of inducing cancer cell apoptosis.

KSP, a member of the kinesin superfamily, mediates centrosome separation and formation of the bipolar mitotic spindle during mitosis. Disruption of this process leads to activation of a 'spindle assembly checkpoint' that prevents the onset of anaphase and results in cell-cycle arrest. KSP inhibitors are therefore being developed as a new generation of antimitotic agents.

Tao et al. performed a high-throughput screen to identify inhibitors of the motor domain of KSP. They discovered a compound, which they named KSP-IA, and showed it to be a specific and cell-permeable small molecule inhibitor of the enzymatic activity of KSP. In ovarian and colon cancer cell lines, KSP-IA activated the spindle checkpoint, leading to mitotic arrest. These effects were reversible — after removal of the drug, cells underwent normal chromosome segregation and cytokinesis. Extending the time of drug treatment to beyond 24 hours, however, caused a significant fraction of cells to undergo apoptosis.

How might disruption of mitotic-spindle function lead to apoptosis? The authors found that in spindle-checkpoint-competent cells, apoptosis induction by prolonged exposure to this drug was coupled with 'mitotic slippage' — a process by which cells, in the presence of persistent spindle damage, override the spindle-checkpoint to exit mitosis and form tetraploid cells. A combination of spindle checkpoint activation followed by mitotic slippage activates the pro-apoptotic protein BAX, mediating the mechanism of cell-death induction in KSP-IA treated cells.

These findings indicate that mitotic slippage, after activation of the spindle checkpoint, increases the lethality of KSP inhibitors. This is similar to the mechanisms of the DNA-damage checkpoint, and has important implications for the development of KSP inhibitors as anticancer drugs.