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

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.

• Authors: Lilach Moyal, Neta Goldfeiz, Batia Gorovitz, Ada Rephaeli, Efrat Tal, Nataly Tarasenko, Abraham Nudelman, Yael Ziv, Emmilia Hodak
• Journal: Investigational new drugs (Invest New Drugs) Vol. 36 Issue 1 Pg. 1-9 (02 2018) ISSN: 1573-0646 [Electronic] United States
• PMID: 28884410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Butyrates
• Histone Deacetylase Inhibitors
• Organophosphorus Compounds
• Prodrugs
• diethoxyphosphoryloxymethyl butanoate
• Doxorubicin

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Butyrates (pharmacology)
• Cell Line, Tumor
• DNA Breaks, Double-Stranded
• DNA Repair (drug effects)
• Doxorubicin (pharmacology)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Lymphoma, T-Cell, Cutaneous (drug therapy)
• Organophosphorus Compounds (pharmacology)
• Prodrugs (pharmacology)
• Skin Neoplasms (drug therapy)