Current and next generation antimitotic therapies in cancer

Abstract

The partitioning of chromosomal and nonchromosomal materials during mitotic cell division represents a dramatic cellular reorganization, and even minor disruptions in the proteins that regulate mitotic progression can adversely impact cell viability. Mitotic cell division thus represents an especially vulnerable point in the life cycle of highly proliferative cancer cells. Perhaps unsurprisingly then, antimitotic agents, specifically those targeting microtubules, are among the oldest and most widely used classes of drugs in the chemotherapeutic arsenal for cancer patient care, with close to two decades of clinical use. The complexities associated with mitotic cell division including the large numbers of proteins associated with this event continue to be better elucidated. Along with this improved understanding come additional opportunities to disrupt the mitotic apparatus for the treatment of cancer beyond direct microtubule perturbing agents. A number of enzyme classes are being considered for this, including kinases, kinesins, GTPases, ubiquitin-like modifiers, and ubiquitin specific proteases (USPs) among others. These new approaches for disrupting the mitotic machinery offer several potential advantages over the traditional antimicrotubule agents; including a narrower spectrum of on-target toxicities, more manageable side effects, a distinct range of sensitive cancers and the promise for improved outcome in combination with other therapeutic modalities.