MLN8054, A small molecule inhibitor of Aurora kinase A, sensitizes androgen-resistant prostate cancer to radiation

Luigi Moretti, Kenneth Niermann, Stephen Schleicher, Nicholas J. Giacalone, Vinod Varki, Kwang Woon Kim, Prapaporn Kopsombut, Dae Kwang Jung, Bo Lu

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1189-1197
Number of pages9
JournalInternational Journal of Radiation Oncology Biology Physics
Volume80
Issue number4
DOIs
StatePublished - Jul 15 2011
Externally publishedYes

Keywords

  • Aurora kinase A
  • MLN8054
  • Prostate cancer
  • Radiation

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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  • Cite this

    Moretti, L., Niermann, K., Schleicher, S., Giacalone, N. J., Varki, V., Kim, K. W., Kopsombut, P., Jung, D. K., & Lu, B. (2011). MLN8054, A small molecule inhibitor of Aurora kinase A, sensitizes androgen-resistant prostate cancer to radiation. International Journal of Radiation Oncology Biology Physics, 80(4), 1189-1197. https://doi.org/10.1016/j.ijrobp.2011.01.060