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Title: MLN8054, A Small Molecule Inhibitor of Aurora Kinase A, Sensitizes Androgen-Resistant Prostate Cancer to Radiation;Aurora kinase A; MLN8054; Prostate cancer; 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 {gamma}-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 {gamma}-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) significantlymore » 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.« less

Authors:
 [1];  [2]; ; ; ; ; ; ;  [1];  [1]
  1. Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee (United States)
  2. (Belgium)
Publication Date:
OSTI Identifier:
21587619
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 80; Journal Issue: 4; Other Information: DOI: 10.1016/j.ijrobp.2011.01.060; PII: S0360-3016(11)00235-5; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANDROGENS; APOPTOSIS; CELL PROLIFERATION; DNA; NEOPLASMS; PROSTATE; RADIOTHERAPY; STRAND BREAKS; TUMOR CELLS; ANDROSTANES; ANIMAL CELLS; BODY; DISEASES; DNA DAMAGES; GLANDS; HORMONES; MALE GENITALS; MEDICINE; NUCLEAR MEDICINE; NUCLEIC ACIDS; ORGANIC COMPOUNDS; ORGANS; RADIOLOGY; STEROID HORMONES; STEROIDS; THERAPY

Citation Formats

Moretti, Luigi, Department of Radiation Oncology, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Niermann, Kenneth, Schleicher, Stephen, Giacalone, Nicholas J., Varki, Vinod, Kim, Kwang Woon, Kopsombut, Prapaporn, Jung, Dae Kwang, and Bo Lu, E-mail: bo.lu@vanderbilt.edu. MLN8054, A Small Molecule Inhibitor of Aurora Kinase A, Sensitizes Androgen-Resistant Prostate Cancer to Radiation;Aurora kinase A; MLN8054; Prostate cancer; Radiation. United States: N. p., 2011. Web. doi:10.1016/j.ijrobp.2011.01.060.
Moretti, Luigi, Department of Radiation Oncology, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Niermann, Kenneth, Schleicher, Stephen, Giacalone, Nicholas J., Varki, Vinod, Kim, Kwang Woon, Kopsombut, Prapaporn, Jung, Dae Kwang, & Bo Lu, E-mail: bo.lu@vanderbilt.edu. MLN8054, A Small Molecule Inhibitor of Aurora Kinase A, Sensitizes Androgen-Resistant Prostate Cancer to Radiation;Aurora kinase A; MLN8054; Prostate cancer; Radiation. United States. doi:10.1016/j.ijrobp.2011.01.060.
Moretti, Luigi, Department of Radiation Oncology, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Niermann, Kenneth, Schleicher, Stephen, Giacalone, Nicholas J., Varki, Vinod, Kim, Kwang Woon, Kopsombut, Prapaporn, Jung, Dae Kwang, and Bo Lu, E-mail: bo.lu@vanderbilt.edu. Fri . "MLN8054, A Small Molecule Inhibitor of Aurora Kinase A, Sensitizes Androgen-Resistant Prostate Cancer to Radiation;Aurora kinase A; MLN8054; Prostate cancer; Radiation". United States. doi:10.1016/j.ijrobp.2011.01.060.
@article{osti_21587619,
title = {MLN8054, A Small Molecule Inhibitor of Aurora Kinase A, Sensitizes Androgen-Resistant Prostate Cancer to Radiation;Aurora kinase A; MLN8054; Prostate cancer; Radiation},
author = {Moretti, Luigi and Department of Radiation Oncology, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels and Niermann, Kenneth and Schleicher, Stephen and Giacalone, Nicholas J. and Varki, Vinod and Kim, Kwang Woon and Kopsombut, Prapaporn and Jung, Dae Kwang and Bo Lu, E-mail: bo.lu@vanderbilt.edu},
abstractNote = {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 {gamma}-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 {gamma}-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.},
doi = {10.1016/j.ijrobp.2011.01.060},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 4,
volume = 80,
place = {United States},
year = {2011},
month = {7}
}