AN-7, a butyric acid prodrug, sensitizes cutaneous T-cell lymphoma cell lines to doxorubicin via inhibition of DNA double strand breaks repair

Lilach Moyal*, Neta Goldfeiz, Batia Gorovitz, Ada Rephaeli, Efrat Tal, Nataly Tarasenko, Abraham Nudelman, Yael Ziv, Emmilia Hodak

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

We previously found that the novel histone deacetylase inhibitor (HDACI) butyroyloxymethyl diethylphosphate (AN-7) had greater selectivity against cutaneous T-cell lymphoma (CTCL) than SAHA. AN-7 synergizes with doxorubicin (Dox), an anthracycline antibiotic that induces DNA breaks. This study aimed to elucidate the mechanism underlying the effect of AN-7 on Dox-induced double-strand DNA breaks (DSBs) in CTCL, MyLa and Hut78 cell lines. The following markers/assays were employed: comet assay; western blot of γH2AX and p-KAP1; immunofluorescence of γH2AX nuclear foci; Western blot of repair protein; quantification of DSBs-repair through homologous recombination. DSB induction by Dox was evidenced by an increase in DSB markers, and DSBs-repair, by their subsequent decrease. The addition of AN-7 slightly increased Dox induction of DSBs in MyLa cells with no effect in Hut78 cells. AN-7 inhibited the repair of Dox-induced DSBs, with a more robust effect in Hut78. Treatment with AN-7 followed by Dox reduced the expression of DSB-repair proteins, with direct interference of AN-7 with the homologous recombination repair. AN-7 sensitizes CTCL cell lines to Dox, and when combined with Dox, sustains unrepaired DSBs by suppressing repair protein expression. Our data provide a mechanistic rationale for combining AN-7 with Dox or other DSB inducers as a therapeutic modality in CTCL.

Original languageEnglish
Pages (from-to)1-9
Number of pages9
JournalInvestigational New Drugs
Volume36
Issue number1
DOIs
StatePublished - 1 Feb 2018

Keywords

  • AN-7
  • Cutaneous T-cell lymphoma (CTCL)
  • Doxorubicin
  • Histone deacetylase inhibitor (HDACI)
  • Mycosis fungoides (MF)
  • Sezary syndrome (SS)

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