Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells.
Histone deacetylase inhibitors (HDACIs) represent a promising new class of antineoplastic agents that affect proliferation, differentiation, and apoptosis in both solid and hematologic malignancies. In addition, HDACIs can alter the expression of at least one cellular adhesion molecule, the coxsackie and adenovirus receptor, in bladder cancer. Because 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 h) 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, because 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 effects by inhibiting invasion as well as tumor growth, and thus it may represent a novel adjuvant strategy for patients at high risk of recurrence and/or progression of muscle invasive bladder cancer.
Chen
Chien-Lun
CL
The Johns Hopkins Hospital, 600 North Wolfe St., Marburg 205, Baltimore, MD 21287, USA.
Sung
Jennifer
J
Cohen
Michael
M
Chowdhury
Wasim H
WH
Sachs
Markus D
MD
Li
Ying
Y
Lakshmanan
Yegappan
Y
Yung
Benjamin Y M
BY
Lupold
Shawn E
SE
Rodriguez
Ronald
R
D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011991:Receptors, Virus / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology*
C493956:CDKN1A protein, human; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011991:Receptors, Virus; D014635:Valproic Acid