Co-treatment with vorinostat synergistically enhances activity of Aurora kinase inhibitor against human breast cancer cells

Abstract

Aurora kinases (AKs) regulate multiple components of mitotic cell division in eukaryotic cells. Aurora A is frequently amplified or overexpressed in breast cancer cells leading to aberrant chromosome segregation, genomic instability, and activation of oncogenic pathways. In the present studies, we determined the effects of treatment with the pan-AK inhibitor MK-0457 and/or the pan-histone deacetylase inhibitor vorinostat against human breast cancer cells that were either ER-, PR-, and HER2- (MDA-MB-468 and MDA-MB-231) or exhibited Aurora A amplification (BT-474 and MDA-MB-231 cells). Treatment with MK-0457 depleted p-AKs levels and their activity, as well as induced G2/M accumulation, DNA endoreduplication, multipolar mitotic spindles, and apoptosis of the breast cancer cells. Similar apoptotic effects were observed with treatment with the Aurora A-specific inhibitor, MLN8237. Treatment with vorinostat induced hsp90 acetylation and inhibited its chaperone association with AKs, leading to depletion of AKs and Survivin. Exposure of the siRNA to AK A also induced apoptosis, which was augmented by co-treatment with MK-0457 and vorinostat. Co-treatment with vorinostat enhanced MK-0457-mediated inhibition of the activities of Aurora A and Aurora B, leading to synergistic in vitro activity against human breast cancer cells. Co-treatment with MK-0457 and vorinostat also caused greater tumor growth inhibition and superior survival of mice bearing MDA-MB-231 xenografts. These pre-clinical findings indicate that combined treatment with a pan-AK inhibitor or an Aurora A-specific inhibitor and vorinostat represents a novel therapeutic strategy for the treatment of Aurora A-amplified and/or triple negative breast cancers.