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While most studies have focused on the reexpression of silenced tumor suppressor genes, a number of genes\/pathways are downregulated by <jats:styled-content style=\"fixed-case\">HDACI<\/jats:styled-content>s. This provides opportunities for combination therapy: agents that further disable these pathways through inhibition of residual gene function are speculated to enhance cell death in combination with <jats:styled-content style=\"fixed-case\">HDACI<\/jats:styled-content>s. A previous study from our group indicated that mitotic checkpoint kinases such as <jats:styled-content style=\"fixed-case\">PLK<\/jats:styled-content>1 and Aurora A are downregulated by <jats:styled-content style=\"fixed-case\">HDACI<\/jats:styled-content>s. We used in vitro and in vivo xenograft models of prostate cancer (<jats:styled-content style=\"fixed-case\">PCA<\/jats:styled-content>) to test whether combination of <jats:styled-content style=\"fixed-case\">HDACI<\/jats:styled-content>s with the pan\u2010aurora kinase inhibitor <jats:styled-content style=\"fixed-case\">AMG<\/jats:styled-content> 900 can synergistically or additively kill <jats:styled-content style=\"fixed-case\">PCA<\/jats:styled-content> cells. <jats:styled-content style=\"fixed-case\">AMG<\/jats:styled-content> 900 and <jats:styled-content style=\"fixed-case\">HDACI<\/jats:styled-content>s synergistically decreased cell proliferation activity and clonogenic survival in <jats:styled-content style=\"fixed-case\">DU<\/jats:styled-content>\u2010145, <jats:styled-content style=\"fixed-case\">LNC<\/jats:styled-content>aP, and <jats:styled-content style=\"fixed-case\">PC<\/jats:styled-content>3 <jats:styled-content style=\"fixed-case\">PCA<\/jats:styled-content> cell lines compared to single\u2010agent treatment. Cellular senescence, polyploidy, and apoptosis was significantly increased in all cell lines after combination treatment. In vivo xenograft studies indicated decreased tumor growth and decreased aurora B kinase activity in mice treated with low\u2010dose <jats:styled-content style=\"fixed-case\">AMG<\/jats:styled-content> 900 and vorinostat compared to either agent alone. Pharmacodynamics was assessed by scoring for phosphorylated histone H3 through immunofluorescence. Our results indicate that combination treatment with low doses of <jats:styled-content style=\"fixed-case\">AMG<\/jats:styled-content> 900 and <jats:styled-content style=\"fixed-case\">HDACI<\/jats:styled-content>s could be a promising therapy for future clinical trials against <jats:styled-content style=\"fixed-case\">PCA<\/jats:styled-content>.<\/jats:p>","DOI":"10.1002\/cam4.289","type":"journal-article","created":{"date-parts":[[2014,7,3]],"date-time":"2014-07-03T07:16:31Z","timestamp":1404371791000},"page":"1322-1335","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Combining the pan\u2010aurora kinase inhibitor <scp>AMG<\/scp> 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer"],"prefix":"10.1002","volume":"3","author":[{"given":"Channing J.","family":"Paller","sequence":"first","affiliation":[{"name":"Department of Oncology The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medical Institutions Baltimore Maryland 21231"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel D.","family":"Wissing","sequence":"additional","affiliation":[{"name":"Department of Oncology The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medical Institutions Baltimore Maryland 21231"},{"name":"Department of Clinical Oncology Leiden University Medical Center Albinusdreef 2 2333 ZA Leiden The Netherlands"},{"name":"Department of Pathology University Medical Center Utrecht Heidelberglaan 100 3584 CX Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Mendonca","sequence":"additional","affiliation":[{"name":"Department of Oncology The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medical Institutions Baltimore Maryland 21231"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anup","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Oncology The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medical Institutions Baltimore Maryland 21231"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oncology The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medical Institutions Baltimore Maryland 21231"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hea\u2010Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oncology The Sidney Kimmel Comprehensive Cancer Center Johns Hopkins Medical Institutions Baltimore Maryland 21231"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine S. 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