Open AccessCombining the pan‐aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer
Author(s) -
Paller Channing J.,
Wissing Michel D.,
Mendonca Janet,
Sharma Anup,
Kim Eugene,
Kim HeaSoo,
Kortenhorst Madeleine S. Q.,
Gerber Stephanie,
Rosen Marc,
Shaikh Faraz,
Zahurak Marianna L.,
Rudek Michelle A.,
Hammers Hans,
Rudin Charles M.,
Carducci Michael A.,
Kachhap Sushant K.
Publication year - 2014
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.289
Subject(s) - histone deacetylase , prostate cancer , cancer research , histone deacetylase 5 , histone deacetylase inhibitor , kinase , histone deacetylase 2 , prostate , cancer , chemistry , medicine , pharmacology , histone , biochemistry , gene
Histone deacetylase inhibitors ( HDACI s) 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 HDACI 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 HDACI s. A previous study from our group indicated that mitotic checkpoint kinases such as PLK 1 and Aurora A are downregulated by HDACI s. We used in vitro and in vivo xenograft models of prostate cancer ( PCA ) to test whether combination of HDACI s with the pan‐aurora kinase inhibitor AMG 900 can synergistically or additively kill PCA cells. AMG 900 and HDACI s synergistically decreased cell proliferation activity and clonogenic survival in DU ‐145, LNC aP, and PC 3 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 HDACI s could be a promising therapy for future clinical trials against PCA .