The inhibitor of histone deacetylases sodium butyrate enhances the cytotoxicity of mitomycin C.
The use of histone deacetylase inhibitors has been proposed as a promising approach to increase the cell killing effect of DNA damage-inducing drugs in chemotherapy. However, the molecular mechanism of their action remains understudied. In the present article, we have assessed the effect of the histone deacetylase inhibitor sodium butyrate on the DNA damage response induced by the crosslinking agent mitomycin C. Sodium butyrate increased mitomycin C cytotoxicity, but did not impair the repair pathways required to remove mitomycin C-induced lesions as neither the rate of nucleotide excision repair nor the homologous recombination repair rate were diminished. Sodium butyrate treatment abrogated the S-phase cell-cycle checkpoint in mitomycin C-treated cells and induced the G(2)-M checkpoint. However, sodium butyrate treatment alone resulted in accumulation of reactive oxygen species, double-strand breaks in DNA, and apoptosis. These results imply that the accumulation of reactive oxygen species-mediated increase in DNA lesion burden may be the major mechanism by which sodium butyrate enhances the cytotoxicity of mitomycin C.
Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G. Bonchev Str. Block 21, 1113 Sofia, Bulgaria. bar@bio21.bas.bg
Anastas
A
Gospodinov
Stanislava
S
Popova
Ivelina
I
Vassileva
Boyka
B
Anachkova
D000818:Animals; D020148:Butyric Acid / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D045325:HCT116 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016685:Mitomycin / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D017382:Reactive Oxygen Species; D020148:Butyric Acid; D016685:Mitomycin