Abstract
The purpose of this study is to investigate a potential new radioenhancer for the treatment of prostate cancer. Despite multiple promising treatment modalities, prostate cancer remains a significant cause of diminished quality of life and cancer death, indicating the need for more aggressive, targeted therapy. Aurora kinase A (AURKA) is a promising treatment target, but its inhibition has never been investigated in combination with radiotherapy in prostate cancer. Using the selective AURKA inhibitor, MLN8054, we performed clonogenic assay to investigate in vitro radiosensitization, cell cycle analysis to observe changes induced by AURKA inhibition, tumor growth delay to study in vivo effects, and histologic active caspase staining to measure apoptosis. We demonstrated radiosensitizing effects in vitro in PC3 and DU145 prostate cancer cell lines, which was confirmed in vivo by tumor growth delay in PC3 xenografts in nude mice. In addition, we investigated a potential mechanism for radiosensitization. We report that MLN8054 induces cell cycle arrest at G2/M and polyploidy in both prostate cancer cell lines, which is associated with sustained DNA damage from radiation as seen by increased immunofluorescence for γ-H2AX, a measure of DNA double-strand breaks. Staining for caspase-3 in xenograft samples showed increased apoptosis in irradiated samples pre-treated with MLN8054 compared to irradiation or inhibitor alone. Our findings support the potential use of AURKA inhibition with MLN8054 to enhance the effectiveness of radiation therapy for the treatment of prostate cancer, and suggest a potential mechanism underlying its radiosensitization effects.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1398.
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