title: Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer.
abstract: Histone deacetylase inhibitors (HDACIs) are being tested in clinical trials for the treatment of solid tumors. While most studies have focused on the reexpression of silenced tumor suppressor genes, a number of genes/pathways are downregulated by HDACIs. 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 HDACIs. A previous study from our group indicated that mitotic checkpoint kinases such as PLK1 and Aurora A are downregulated by HDACIs. We used in vitro and in vivo xenograft models of prostate cancer (PCA) to test whether combination of HDACIs with the pan-aurora kinase inhibitor AMG 900 can synergistically or additively kill PCA cells. AMG 900 and HDACIs synergistically decreased cell proliferation activity and clonogenic survival in DU-145, LNCaP, and PC3 PCA cell lines compared to single-agent 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-dose AMG 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 AMG 900 and HDACIs could be a promising therapy for future clinical trials against PCA.
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, 21231.
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Paller
authors.forename: Michel D
authors.initials: MD
authors.lastname: Wissing
authors.forename: Janet
authors.initials: J
authors.lastname: Mendonca
authors.forename: Anup
authors.initials: A
authors.lastname: Sharma
authors.forename: Eugene
authors.initials: E
authors.lastname: Kim
authors.forename: Hea-Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Madeleine S Q
authors.initials: MS
authors.lastname: Kortenhorst
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gerber
authors.forename: Marc
authors.initials: M
authors.lastname: Rosen
authors.forename: Faraz
authors.initials: F
authors.lastname: Shaikh
authors.forename: Marianna L
authors.initials: ML
authors.lastname: Zahurak
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Hans
authors.initials: H
authors.lastname: Hammers
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Sushant K
authors.initials: SK
authors.lastname: Kachhap
mesh_terms: D000818:Animals; D064127:Aurora Kinases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology*; D011123:Polyploidy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008941:Spindle Apparatus / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; C555658:N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases
keywords: AMG 900; aurora kinase inhibitor; histone deacetylase inhibitors; prostate cancer; synergy; valproic acid; vorinostat