Combining the pan‐aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer

Cancer Medicine

Channing J. Paller¹  Michel D. Wissing¹  Janet Mendonca¹  Anup Sharma¹  Eugene Kim¹  Hea-Soo Kim¹  Madeleine S. Q. Kortenhorst¹  Stephanie Gerber¹  Marc Rosen¹  Faraz Shaikh³  Marianna L. Zahurak²  Michelle A. Rudek¹  Hans Hammers¹  Charles M. Rudin¹  Michael A. Carducci¹ 

[1] Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland;Department of Oncology Biostatistics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland;School of Medicine, Eastern Virginia Medical School, Norfolk, Virginia

关键词: AMG 900;    aurora kinase inhibitor;    histone deacetylase inhibitors;    prostate cancer;    synergy;    valproic acid;    vorinostat;   

DOI  :  10.1002/cam4.289

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.