MLN8054, a small molecule inhibitor of aurora kinase a, sensitizes androgen-resistant prostate cancer to radiation.

Abstract

PURPOSE:

To determine whether MLN8054, an Aurora kinase A (Aurora-A) inhibitor causes radiosensitization in androgen-insensitive prostate cancer cells in vitro and in vivo.

METHODS AND MATERIALS:

In vitro studies consisted of culturing PC3 and DU145 prostate cancer cells and then immunoblotting Aurora A and phospho-Aurora A after radiation and/or nocodazole with MLN8054. Phases of the cell cycle were measured with flow cytometry. PC3 and DU145 cell lines were measured for survival after treatment with MLN8054 and radiation. Immunofluorescence measured γ-H2AX in the PC3 and DU145 cells after treatment. In vivo studies looked at growth delay of PC3 tumor cells in athymic nude mice. PC3 cells grew for 6 to 8 days in mice treated with radiation, MLN8054, or combined for 7 more days. Tumors were resected and fixed on paraffin and stained for von Willebrand factor, Ki67, and caspase-3.

RESULTS:

In vitro inhibition of Aurora-A by MLN8054 sensitized prostate cancer cells, as determined by dose enhancement ratios in clonogenic assays. These effects were associated with sustained DNA double-strand breaks, as evidenced by increased immunofluorescence for γ-H2AX and significant G2/M accumulation and polyploidy. In vivo, the addition of MLN8054 (30 mg/kg/day) to radiation in mouse prostate cancer xenografts (PC3 cells) significantly increased tumor growth delay and apoptosis (caspase-3 staining), with reduction in cell proliferation (Ki67 staining) and vascular density (von Willebrand factor staining).

CONCLUSION:

MLN8054, a novel small molecule Aurora-A inhibitor showed radiation sensitization in androgen-insensitive prostate cancer in vitro and in vivo. This warrants the clinical development of MLN8054 with radiation for prostate cancer patients.

• Authors: Luigi Moretti, Kenneth Niermann, Stephen Schleicher, Nicholas J Giacalone, Vinod Varki, Kwang Woon Kim, Prapaporn Kopsombut, Dae Kwang Jung, Bo Lu
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 80 Issue 4 Pg. 1189-97 (Jul 15 2011) ISSN: 1879-355X [Electronic] United States
• PMID: 21514073 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Androgens
• Benzazepines
• H2AX protein, human
• Histones
• Ki-67 Antigen
• MLN8054
• Radiation-Sensitizing Agents
• AURKA protein, human
• Aurka protein, mouse
• Aurora Kinase A
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Caspase 3
• Nocodazole

Topics

• Androgens (therapeutic use)
• Animals
• Apoptosis (radiation effects)
• Aurora Kinase A
• Aurora Kinases
• Benzazepines (therapeutic use)
• Caspase 3 (analysis)
• Cell Cycle
• Cell Line, Tumor
• Cell Survival (drug effects, radiation effects)
• DNA Breaks, Double-Stranded
• Drug Resistance, Neoplasm (drug effects)
• Histones (analysis)
• Humans
• Immunoblotting (methods)
• Ki-67 Antigen (analysis)
• Male
• Mice
• Mice, Nude
• Nocodazole (therapeutic use)
• Prostatic Neoplasms (drug therapy, pathology, radiotherapy)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Radiation Tolerance (drug effects)
• Radiation-Sensitizing Agents (therapeutic use)