Received for publication May 16, 2006.
Revised July 6, 2006.
Accepted for publication July 21, 2006.

Valproic Acid Inhibits Invasiveness in Bladder Cancer, but not in Prostate Cancer Cells

Abstract

Histone deacetylase inhibitors (HDACIs) represent a promising new class of antineoplastic agents that affect proliferation, differentiation, and apoptosis in both solid and haemotologic malignancies. In addition, HDACIs can alter the expression of at least one cellular adhesion molecule, the Coxsackie and Adenovirus Receptor (CAR), in bladder cancer. Since HDACIs can increase expression of a known cellular adhesion molecule, we hypothesized that migration and/or invasion may also be affected. We evaluated this hypothesis using valproic acid (VPA), a commonly prescribed anticonvulsant recently shown to have potent HDACI activity, in the bladder cancer cell lines T24, TCC-SUP, HT1376, and RT4. Analyses of cell migration and invasion were both qualitative (fluorescent microscopy) and quantitative (static and dynamic migration/invasion assays). Our results show that acute VPA treatment (72 hours) causes a dose dependent decrease in invasion for all bladder cancer cell lines, except RT4, a noninvasive papilloma. Migration, in contrast, was not affected by VPA treatment. The inhibitory effect of VPA may be cancer type specific as there was no difference in invasion between treated and untreated prostate cancer cell lines, LNCaP, PC3 and DU145. Furthermore, when administered chronically (34 days), VPA significantly inhibits growth of T24t tumor xenografts. Our data suggest that VPA exerts some of its antineoplastic effect by inhibiting invasion, as well as tumor growth, and thus may represent a novel adjuvant strategy for patients at high risk of recurrence and/or progression of muscle invasive bladder cancer.

Key words: Bladder cancer, Histone deacetylase inhibitors, Invasion, Migration, Prostate cancer, Valproic acid