Androgen deprivation followed by acute androgen stimulation selectively sensitizes AR-positive prostate cancer cells to ionizing radiation

Mohammad Hedayati, Michael C. Haffner, Jonathan B. Coulter, Raju R. Raval, Yonggang Zhang, Haoming Zhou, Omar Mian, Emma J. Knight, Nina Razavi, Susan Dalrymple, John Tod Isaacs, Aileen Santos, Russell Hales, William G Nelson, S Yegnasubramanian, Theodore DeWeese

Research output: Contribution to journalArticle

Abstract

Purpose: The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen-deprived prostate cancer cells leads to formation of double-strand breaks (DSB). Here, we exploit this finding and investigate the extent and timing of androgen-induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR). Experimental Design: Androgen-induced DNA damage was assessed by comet assays and γH2A.X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models. Results: We document that androgen treatment of androgen-deprived prostate cancer cell lines resulted in a dose- and time-dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor and topoisomerase II beta but not on cell-cycle progression. In vitro models demonstrated a synergistic interaction between IR and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice. Conclusions: These results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy.

Original languageEnglish (US)
Pages (from-to)3310-3319
Number of pages10
JournalClinical Cancer Research
Volume22
Issue number13
DOIs
StatePublished - Jul 1 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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