Valproic Acid Inhibits Invasiveness in Bladder Cancer but Not in Prostate Cancer Cells
- Chien-Lun Chen,
- Jennifer Sung,
- Michael Cohen,
- Wasim H. Chowdhury,
- Markus D. Sachs,
- Ying Li,
- Yegappan Lakshmanan,
- Benjamin Y. M. Yung,
- Shawn E. Lupold and
- Ronald Rodriguez
- James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland (C.-L.C., J.S., M.C., W.H.C., M.D.S., Y.Li., Y.La., S.E.L., R.R.); Department of Urology, Chang Gung Memorial Hospital and Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taipei, Taiwan (C.-L.C.); and Department of Pharmacology, Cancer Biochemistry Laboratory, College of Medicine, Chang Gung University, Taipei, Taiwan (B.Y.M.Y.)
- Address correspondence to:
Dr. Ronald Rodriguez, The Johns Hopkins Hospital, 600 North Wolfe St., Marburg 205, Baltimore, MD 21287. E-mail: rrodriguez{at}jhmi.edu
Abstract
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.
Footnotes
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This work is supported by funding from the Flight Attendant Medical Research Institute.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.106658.
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ABBREVIATIONS: HAT, histone acetyltransferase; HDAC, histone deacetylase; HDACI, histone deacetylase inhibitor; CAR, coxsackie and adenovirus receptor; VPA, valproic acid, 2-propylpentanoic acid; FBS, fetal bovine serum; CFDA SE, carboxyfluorescein diacetate, succinimidyl ester; TSA, trichostatin A; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; FU, fluorescent unit.
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- Received May 15, 2006.
- Accepted July 21, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
