Chromatin remodeling, cell proliferation and cell death in valproic acid-treated HeLa cells.
BACKGROUND
Valproic acid (VPA) is a potent anticonvulsant that inhibits histone deacetylases. Because of this inhibitory action, we investigated whether VPA would affect chromatin supraorganization, mitotic indices and the frequency of chromosome abnormalities and cell death in HeLa cells.


RESULTS
Image analysis was performed by scanning microspectrophotometry for cells cultivated for 24 h, treated with 0.05, 0.5 or 1.0 mM VPA for 1-24 h, and subjected to the Feulgen reaction. TSA-treated cells were used as a predictable positive control. DNA fragmentation was investigated with the TUNEL assay. Chromatin decondensation was demonstrated under TSA and all VPA treatments, but no changes in chromosome abnormalities, mitotic indices or morphologically identified cell death were found with the VPA treatment conditions mentioned above, although decreased mitotic indices were detected under higher VPA concentration and longer exposure time. The frequency of DNA fragmentation identified with the TUNEL assay in HeLa cells increased after a 24-h VPA treatment, although this fragmentation occurred much earlier after treatment with TSA.


CONCLUSIONS
The inhibition of histone deacetylases by VPA induces chromatin remodeling in HeLa cells, which suggests an association to altered gene expression. Under VPA doses close to the therapeutic antiepileptic plasma range no changes in cell proliferation or chromosome abnormalities are elicited. The DNA fragmentation results indicate that a longer exposure to VPA or a higher VPA concentration is required for the induction of cell death.
Department of Structural and Physiological Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Marina Barreto
MB
Felisbino
Wirla M S C
WM
Tamashiro
Maria Luiza S
ML
Mello
D000927:Anticonvulsants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D002869:Chromosome Aberrations / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D015162:Micronucleus Tests; D008938:Mitosis / Q000187:drug effects; D057054:Molecular Imaging; D014635:Valproic Acid / Q000494:pharmacology*
D000927:Anticonvulsants; D014635:Valproic Acid