| Literature DB >> 24950801 |
Hoi Tang Ma1, Sergio Erdal1, Shan Huang1, Randy Y C Poon2.
Abstract
The mitotic kinesin KIF11 (also called Eg5) plays critical roles in spindle functions. Although a number of small-molecule inhibitors of KIF11 are currently in clinical development, drug-resistance could be developed through compensation by another kinesin called KIF15. Using a newly developed infrared-based cell system, we discovered that the effectiveness of one of the latest generations of KIF11 inhibitor (SB743921) could be enhanced with several inhibitors of Aurora A kinase. Evidence including live-cell imaging and isobologram analysis indicated that targeting KIF11 and Aurora A together promoted monoastral spindle formation and mitotic catastrophe synergistically, supporting a model of parallel pathways of centrosome regulation by Aurora A and KIF11. We also developed a KIF15-dependent SB743921-resistance cell model. Significantly, the drug-resistance could also be overcome with Aurora A inhibitors. These results provide a molecular basis for increasing the effectiveness of Aurora A and KIF11 inhibitors and tackling problems of drug resistance.Entities:
Keywords: Drug screening; Drug-resistance; Eg5; Infrared; Kinesin; Mitosis
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Year: 2014 PMID： 24950801 PMCID： PMC5528592 DOI： 10.1016/j.molonc.2014.05.007
Source DB: PubMed Journal: Mol Oncol ISSN： 1574-7891 Impact factor: 6.603