title: 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.
authors: The University of Kansas Cancer Center, 3901 Rainbow Blvd. Robinson Hall 4030, Mail Stop 1027, Kansas City, KS, USA.
authors: Warren
authors: W
authors: Fiskus
authors: Stacey L
authors: SL
authors: Hembruff
authors: Rekha
authors: R
authors: Rao
authors: Priyanka
authors: P
authors: Sharma
authors: Ramesh
authors: R
authors: Balusu
authors: Sreedhar
authors: S
authors: Venkannagari
authors: Jacqueline E
authors: JE
authors: Smith
authors: Karissa
authors: K
authors: Peth
authors: Stephen C
authors: SC
authors: Peiper
authors: Kapil N
authors: KN
authors: Bhalla
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018628:Gene Dosage; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010879:Piperazines / Q000008:administration & dosage; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000077022:Survivin; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D018841:HSP90 Heat-Shock Proteins; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D000077022:Survivin; D000077337:Vorinostat; C107489:BIRC5 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse