Multiple Molecular pathways explain the anti-proliferative effect of valproic acid on prostate cancer cells in vitro and in vivo.
BACKGROUND
Valproic acid (VPA), is a drug approved by the FDA for epilepsy and bipolar disorders. It is a known Histone Deacetylase Inhibitor (HDACI). We tested VPA, for its anti-proliferative activity in prostate cancer (PCa) cell lines in vitro and in vivo.


METHODS
DU-145 and PC-3 PCa cell lines were cultured with different doses of VPA. Cells were examined for their viability, cell cycle status and expression of cell cycle arrest, and proliferation markers. Nude mice bearing xenografts of human PCa cell lines, DU-145, and PC-3, were administered VPA in their drinking water.


RESULTS
VPA displayed a dose- and time-dependent anti-proliferative effect on DU-145 and PC-3 PCa cell lines in vitro. A sustained effect of the drug was seen on cell cycle arrest even at 24 hr after removal of the drug, after which the effects returned to the basal state. Administration of 0.4% w/v VPA in drinking water (resulting in 0.4 mM VPA, in plasma) was effective in inducing growth arrest, cell death, and senescence in vivo and was also anti-angiogenic. The activation of all or some of these anti-proliferative pathways may be contingent on acetylation status of histones, confirmed by detection of increased acetyl-H3K9 in VPA-treated samples when compared with untreated controls. Pharmacodynamic studies showed an increase in expression of p21 and decrease in PCNA in xenografts of VPA-treated mice compared with protein expression in untreated controls.


CONCLUSIONS
VPA may be functioning as an HDACI to inhibit growth of PCa cells in vitro and in vivo by modulating multiple pathways including cell cycle arrest, apoptosis, angiogenesis, and senescence.
Shabbeer
Shabana
S
Prostate Cancer Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland 21231, USA.
Kortenhorst
Madeleine S Q
MS
Kachhap
Sushant
S
Galloway
Nathan
N
Rodriguez
Ron
R
Carducci
Michael A
MA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000473:pathology*; D014635:Valproic Acid / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D014635:Valproic Acid; D006655:Histone Deacetylases