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HDAC Inhibitor Sodium Butyrate Attenuates the DNA Repair in Transformed but Not in Normal Fibroblasts
Olga O Gnedina1, Alisa V Morshneva1, Elena V Skvortsova1
1Institute of Cytology, Russian Academy of Sciences, 194064 St. Petersburg, Russia.
Abstract:
Many cancer therapy strategies cause DNA damage leading to the death of tumor cells. The DNA damage response (DDR) modulators are considered as promising candidates for use in combination therapy to enhance the efficacy of DNA-damage-mediated cancer treatment. The inhibitors of histone deacetylases (HDACis) exhibit selective antiproliferative effects against transformed and tumor cells and could enhance tumor cell sensitivity to genotoxic agents, which is partly attributed to their ability to interfere with DDR. Using the comet assay and host-cell reactivation of transcription, as well as γH2AX staining, we have shown that sodium butyrate inhibited DNA double-strand break (DSB) repair of both endo- and exogenous DNA in transformed but not in normal cells. According to our data, the dysregulation of the key repair proteins, especially the phosphorylated Mre11 pool decrease, is the cause of DNA repair impairment in transformed cells. The inability of HDACis to obstruct DSB repair in normal cells shown in this work demonstrates the advantages of HDACis in combination therapy with genotoxic agents to selectively enhance their cytotoxic activity in cancer cells.
Insights
Histone deacetylase inhibitors (HDACis) selectively impair DNA double-strand break (DSB) repair in cancer cells but not normal cells. This selective inhibition enhances cancer therapy efficacy when combined with genotoxic agents.
Area of Science:
- Cancer Biology
- Molecular Oncology
- DNA Damage Response
Background:
- Cancer therapies often induce DNA damage to kill tumor cells.
- DNA damage response (DDR) modulators are explored for combination therapy.
- Histone deacetylase inhibitors (HDACis) show selective anti-cancer effects and can enhance sensitivity to genotoxic agents by interfering with DDR.
Purpose of the Study:
- To investigate the effect of HDACis on DNA double-strand break (DSB) repair in cancer cells.
- To determine if HDACis selectively impair DNA repair in transformed versus normal cells.
- To elucidate the mechanism behind impaired DNA repair in transformed cells treated with HDACis.
Main Methods:
- Comet assay to assess DNA double-strand breaks (DSBs).
- Host-cell reactivation of transcription assays.
- Gamma-H2AX (γH2AX) staining to visualize DNA damage foci.
- Analysis of key DNA repair protein levels, including phosphorylated Mre11.
Main Results:
- Sodium butyrate, an HDACi, inhibited the repair of both endogenous and exogenous DNA double-strand breaks (DSBs) in transformed cells.
- This inhibition of DSB repair was not observed in normal cells treated with sodium butyrate.
- Impaired DNA repair in transformed cells was linked to dysregulation of key repair proteins, specifically a decrease in the phosphorylated Mre11 pool.
Conclusions:
- HDACis selectively impair DNA double-strand break (DSB) repair in transformed cancer cells, but not in normal cells.
- This selective action of HDACis offers a therapeutic advantage for combination strategies.
- HDACis can enhance the cytotoxic activity of genotoxic agents specifically in cancer cells, improving treatment efficacy and potentially reducing side effects.
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