Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression.
BACKGROUND
Prevention of bladder cancer recurrence is a central challenge in the management of this highly prevalent disease. The histone deacetylase inhibitor valproic acid (sodium valproate) has anti-angiogenic properties and has been shown to decrease bladder cancer growth in model systems. We have previously shown reduced expression of thrombospondin-1 in a mouse model and in human bladder cancer relative to normal urothelium. We speculated that inhibition of angiogenesis by valproate might be mediated by this anti-angiogenic protein.


METHODS
Bladder cancer cell lines UMUC3 and T24 were treated with valproate or another histone deacetylase inhibitor, vorinostat, in culture for a period of three days. Proliferation was assessed by alamar blue reduction. Gene expression was evaluated by reverse transcription of RNA and quantitative PCR.


RESULTS
Proliferation assays showed treatment with valproate or vorinostat decreased proliferation in both cell lines. Histone deacetylase inhibition also increased relative expression of thrombospondin-1 up to 8 fold at 5 mM valproate.


CONCLUSIONS
Histone deacetylase inhibitors warrant further study for the prevention or treatment of bladder cancer.
Department of Urology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Timothy K
TK
Byler
Dean
D
Leocadio
Oleg
O
Shapiro
Gennady
G
Bratslavsky
Christopher J
CJ
Stodgell
Ronald W
RW
Wood
Edward M
EM
Messing
Jay E
JE
Reeder
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019700:Thrombospondin 1 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014571:Urologic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
D019700:Thrombospondin 1; D014635:Valproic Acid