Spindle Assembly Checkpoint Proteins May Be Targeted by New Anticancer Drugs

Data published in a recent paper on the molecular factors that control chromosome segregation during cell division may help drug developers in their efforts to replace the taxane family of chemotherapeutic agents with similarly effective but less toxic drugs.

The primary taxane is paclitaxel, a naturally occurring compound originally extracted from the bark of the Pacific yew tree (Taxus spp.). Due to high demand, paclitaxel is typically synthesized from the more abundant, naturally occurring compound 10-deacetyl baccatin III, which is extracted from the needles of yew plants. Paclitaxel and the closely related compound docetaxel disrupt microtubule function, which inhibits replication of cancer cells. However, this class of drug can have debilitating side effects including permanent neurological damage and hair loss.

Fine-tuning of drugs to replace the taxanes requires better understanding of the molecular processes that control chromosome segregation during cell division. To this end investigators at the University of Warwick (United Kingdom) have been studying the alphabet soup of proteins – including Mad1, Mad2, Mad3 (BubR1), Bub3, and the kinases Bub1, Mph1 (Mps1), and Aurora B – that comprise the spindle assembly checkpoint (SAC). SAC is the major surveillance system that ensures that sister chromatids do not separate until all chromosomes are correctly oriented during mitosis.

Details of how these proteins interact to maintain SAC activity were published in the April 19, 2012, online edition of the journal Current Biology.

Senior author Dr. Jonathan Millar, professor of cell biology at the University of Warwick said, “Components of the spindle assembly checkpoint were first discovered 22 years ago by researchers in America and yet, until now, the binding sites for these proteins on chromosomes have remained unknown. We have been able to answer this question and as a result, we are now in a much better position to design more selective and effective drugs. This research is a significant advance in our understanding of how the spindle checkpoint operates but it is really just the start. More research has to be done before we can convert this into a commercial treatment for patients. But we are greatly encouraged that our research here at Warwick is leading the way in the search for more effective cancer drugs.”

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