Valproic acid as a therapeutic agent for head and neck squamous cell carcinomas.
OBJECTIVE
Here we investigate if valproic acid (VA) can enhance the efficacy of commonly used therapies for head and neck squamous cell carcinomas (HNSCC) and the molecular mechanisms that may be related to its anticancer effects.


METHODS
Proliferation and viability of distinct cell types subjected to VA treatment alone or in combination regimens were measured through BrdU incorporation and LDH release, respectively. Molecular markers compatible with histone deacetylase inhibitory activity of VA were assessed through western blots assays in lysates obtained from cultured cells and tumour biopsies.


RESULTS
Treatment of all cell types with VA resulted in a dose-dependent increase in histone H3 acetylation and p21 expression, as well as dose-dependent cytostasis. In contrast, the cytotoxic response to VA was variable and did not correlate with cytostasis, histone acetylation or p21 induction. The variability in response to VA was also observed in tumour biopsy samples collected from patients prior to and following a 1 week oral course of VA. In addition, we found that a combination of a clinically achievable concentration of VA plus cisplatin caused a threefold to sevenfold increase in cisplatin cytotoxicity in vitro.


CONCLUSIONS
VA acts as a histone deacetylase inhibitor (HDI) in SCC cells and normal human keratinocytes (HKs), potentiates the cytotoxic effect of cisplatin in SCC cell lines and decreases the viability of SCC cells as opposed to HKs. Taken together, the results provide initial evidence that VA might be a valuable drug in the development of better therapeutic regimens for HNSCC.
Erlich
Rafael B
RB
Epithelial Pathobiology Group, Cancer Biology Programme, Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia.
Rickwood
Danny
D
Coman
William B
WB
Saunders
Nicholas A
NA
Guminski
Alexander
A
D000107:Acetylation; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D014635:Valproic Acid