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

Channing J. Paller, Michel D. Wissing, Janet Mendonca, Anup Sharma, Eugene Kim, Hea Soo Kim, Madeleine S.Q. Kortenhorst, Stephanie Gerber, Marc Rosen, Faraz Shaikh, Marianna L. Zahurak, Michelle A. Rudek, Hans Hammers, Charles M. Rudin, Michael A. Carducci, Sushant K. Kachhap

Research output: Contribution to journalArticle

15 Citations (Scopus)

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. Combination therapy consisting of AMG 900, a pan-aurora kinase inhibitor, with the histone deacetylase inhibitors (HDACIs) valproic acid (VPA), and vorinostat (SAHA) was tested in prostate cancer cells. In vitro, the combination had synergistic antitumor activity. In vivo studies indicated decreased tumor growth in mice treated with low-dose AMG 900 and vorinostat compared to either agent alone.

Original languageEnglish (US)
Pages (from-to)1322-1335
Number of pages14
JournalCancer Medicine
Volume3
Issue number5
DOIs
StatePublished - Oct 1 2014

Fingerprint

Aurora Kinases
Histone Deacetylase Inhibitors
Prostatic Neoplasms
Heterografts
Therapeutics
Down-Regulation
Aurora Kinase B
Clinical Trials
M Phase Cell Cycle Checkpoints
Cell Line
Neoplasms
Polyploidy
N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine
Cell Aging
Valproic Acid
Growth
Tumor Suppressor Genes
Histones
Genes
Fluorescent Antibody Technique

Keywords

  • AMG 900
  • Aurora kinase inhibitor
  • Histone deacetylase inhibitors
  • Prostate cancer
  • Synergy
  • Valproic acid
  • Vorinostat

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Paller, C. J., Wissing, M. D., Mendonca, J., Sharma, A., Kim, E., Kim, H. S., ... Kachhap, S. K. (2014). Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer. Cancer Medicine, 3(5), 1322-1335. https://doi.org/10.1002/cam4.289

Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer. / Paller, Channing J.; Wissing, Michel D.; Mendonca, Janet; Sharma, Anup; Kim, Eugene; Kim, Hea Soo; 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.

In: Cancer Medicine, Vol. 3, No. 5, 01.10.2014, p. 1322-1335.

Research output: Contribution to journalArticle

Paller, CJ, Wissing, MD, Mendonca, J, Sharma, A, Kim, E, Kim, HS, Kortenhorst, MSQ, Gerber, S, Rosen, M, Shaikh, F, Zahurak, ML, Rudek, MA, Hammers, H, Rudin, CM, Carducci, MA & Kachhap, SK 2014, 'Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer', Cancer Medicine, vol. 3, no. 5, pp. 1322-1335. https://doi.org/10.1002/cam4.289
Paller, Channing J. ; Wissing, Michel D. ; Mendonca, Janet ; Sharma, Anup ; Kim, Eugene ; Kim, Hea Soo ; 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. / Combining the pan-aurora kinase inhibitor AMG 900 with histone deacetylase inhibitors enhances antitumor activity in prostate cancer. In: Cancer Medicine. 2014 ; Vol. 3, No. 5. pp. 1322-1335.
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