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

作者：Moyal Lilach^*; Goldfeiz Neta; Gorovitz Batia; Rephaeli Ada; Tal Efrat; Tarasenko Nataly; Nudelman Abraham; Ziv Yael; Hodak Emmilia

来源：Investigational New Drugs, 2018, 36(1): 1-9.

DOI：10.1007/s10637-017-0500-x

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

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 gamma H2AX and p-KAP1; immunofluorescence of gamma H2AX 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.

• 出版日期2018-2