A combined pretreatment of 1,25-dihydroxyvitamin D3 and sodium valproate enhances the damaging effect of ionizing radiation on prostate cancer cells

Vladimir Gavrilov, Yaron Leibovich, Samuel Ariad, Konstantin Lavrenkov, Shraga Shany

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Radiotherapy is one of the curative treatment options for prostate cancer (PCa). However, effective doses of ionizing radiation (IR) have a high risk of side effects. To increase sensitivity of PCa to IR we pretreated human androgen-refractory DU145 PCa cells with a combination of sodium valproate (VPA), a well-tolerated drug with histone deacetylases inhibiting activity, and 1,25-dihydroxyvitamin D3, 1,25(OH)2D3, the active metabolite of vitamin D, a well known anticancer agent. The results show that irradiation (4. Gy) of DU145 PCa cells pretreated with a combination of 1. mM VPA and 100. nM 1,25(OH)2D3 efficiently suppressed (87.9%) PCa cell proliferation. IR after combined pretreatment resulted in increased DNA double-strand breaks expressed as levels of phosphorylated histone H2A.X, compared with non-treated cells the increase was 58.1% in pretreated cells and 11.8% in non-pretreated cells (p<0.002). Combined pretreatment enhanced IR-induced activation of DNA damage checkpoint kinase Chk2, 39.0% in pretreated cells compared to 23.8% in non-pretreated cells (p<0.05). These molecular changes led to DNA replication blockade, S-phase cell-cycle arrest and enhanced apoptosis. Cumulatively, the results indicate that combined pretreatment with VPA and 1,25(OH)2D3 followed by IR is a highly effective treatment for human PCa cells. This observation may have important implications for reducing doses of radiation administered to cancer patients thus limiting the severity of side effects.

Original languageEnglish
Pages (from-to)391-394
Number of pages4
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume121
Issue number1-2
DOIs
StatePublished - 1 Jul 2010

Keywords

  • 1,25-Dihydroxyvitamin D3
  • Histone deacetylase inhibitor
  • Ionizing radiation
  • Prostate cancer
  • Sodium valproate

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

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