Beyond genetics: surprising determinants of cell fate in antitumor drugs

Abstract

In this issue of Cancer Cell, Gascoigne and Taylor (2008) report their findings of following 10,000 single cells incubated with three classes of antimitotic drugs, including paclitaxel (taxol). This extensive analysis reveals a previously unappreciated complexity in response to such drugs and demonstrates that it is more than genetics that determines cell life or death.

Figure 1

Model for two competing networks that together dictate mitotic cell fate. A. Cyclin B1 (blue) is progressively destroyed during a mitotic delay and at the same time a putative death signal (possibly also produced by the mitotic checkpoint) accumulates (red). Eventually cyclin B1 levels fall bellow a threshold required to maintain mitotic arrest and the cell (e.g., a retinal pigmented epithelial [RPE] cell) undergoes adaptation. B. Cyclin B1 levels fall during mitotic delay, but fail to decline to the threshold required to allow mitotic exit. Instead, the apoptotic signal reaches a level sufficient to promote cell death in mitosis (e.g., HT29 cell). C. Slowing the activation of apoptotic effectors by treatment with a caspase inhibitor provides (e.g., the HT29 cell) with more time to destroy cyclin B1. This allows cyclin B1 levels to reach the threshold required to promote mitotic exit before apoptosis is initiated.