Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression
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.
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.
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.
Histone deacetylase inhibitors warrant further study for the prevention or treatment of bladder cancer.
- SEER Public-Use 1973–2002, Surveillance, Epidemiology, and End Results (SEER) Program () Public-Use Data (1973–2002). www.seer.cancer.gov National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch; released April 2005, based on the November 2004 submissionSEER Public-Use 1973–2002, Surveillance, Epidemiology, and End Results (SEER) Program () Public-Use Data (1973–2002). www.seer.cancer.gov National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch; released April 2005, based on the November 2004 submission SEER Public-Use 1973–2002, Surveillance, Epidemiology, and End Results (SEER) Program () Public-Use Data (1973–2002). National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch; released April 2005, based on the November 2004 submission
- Babjuk M, Oosterlinck W, Sylvester R, Kaasinen E, Bohle A, Palou-Redorta J, Roupret M: EUA Guidelines on non-muscle invasive urothelial carcinoma of the bladder, the 2011 update. Eur Urol 2011, 59:997–1008. CrossRef
- Das CM, Aguilera D, Vasquez H, Prasad P, Zhang M, Wolff JE, Gopalakrishnan V: Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. J Neurooncol 2007, 85:159–170. CrossRef
- Catalano MG, Fortunati N, Pugliese M, Poli R, Bosco O, Mastrocola R, Aragano M, Boccuzzi G: Valproic acid, a histone deacetylase inhibitor, enhances sensitivity to doxorubicin in anaplastic thyroid cancer cells. J Endocrinol 2006, 191:465–472. CrossRef
- Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, et al.: Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 2007, 110:2302–2308. CrossRef
- Chen CL, Sung J, Cohen M, Chowdhury WH, Sachs MD, Li Y, Kakshmanan Y, Yung BYM, Lupold SE, Rodriguez R, Cortes J, Wierda WG, Quezada A, Pierce S, Estey EH, Issa JP, Kantarjian HM, Gardia-Manero G: Valproic acid inhibits invasiveness in bladder cancer but not in prostate cancer cells. J Pharmacol Exp Ther 2006, 319:533–542. CrossRef
- Byun SS, Kim FJ, Khandrika L, Kumar B, Koul S, Wilson S, Koul HK: Differential effects of valproic acid on growth proliferation and metastasis in HTB5 and HTB9 bladder cancer cell lines. Cancer Lett 2009, 281:196–202. CrossRef
- Ozawa A, Tanji N, Kikugawa T, Sasaki T, Yanagihara Y, Miura N, Yokoyama M: Inhibition of bladder tumour growth by histone deacetylase inhibitor. BJU Int 2010, 105:1181–1186. CrossRef
- Vallo S, Xi W, Juengel E, Tsaur I, Wiesner C, Haferkamp A, Blaheta RA: HDAC inhibition delays cell cycle progression of human bladder cancer cells in vitro. Anti-Cancer Drugs 2011, 22:1002–1009.
- Dawson DW, Volpert OV, Pearce FA, Schneider AJ, Silverstein RL, Henkin J, Bouck N: Three distinct D-amino acid substitutions confer potent anti-angiogenic activity on an inactive peptide dervived from a Thrombospondin-1 type 1 repeat. Mol Pharmacol 1999, 55:332–338.
- Grossfeld GD, Ginsberg DA, Stein JP, Bochner BH, Esrig D, Groshen S, Dunn M, Nichols PW, Taylor CR, Skinner DG, Cote RJ: Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression. JNCI 1997, 89:219–227. CrossRef
- Campbell SC, Bolpert OV, Ivanovich M, Bouck NP: Molecular mediators of angiogenesis in bladder cancer. Cancer Res 1998, 58:1298–1304.
- Johnson AM, O’Connell MJ, Miyamoto H, Huang J, Yao JL, Messing EM, Reeder JE: Androgeneic dependence of exophytic tumor growth in a transgenic mouse model of bladder cancer: a role for thrombospondin-1. BMC Urol 2008, 8:7. CrossRef
- Zhang ZT, Pak J, Shapiro E, Sun TT, Wu XR: Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. Cancer Res 1999, 52:3512–3517.
- Andersen CL, Jensen JL, Orntoft TF: Normalization of real-time quantitative reverse transcription-PCR data: A model based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data. Cancer Res 2004, 64:5245–5250. CrossRef
- Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002, 3:1–12. CrossRef
- Livak KJ, Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 2001, 25:402–408. CrossRef
- Ioachim E, Michael MC, Salmas M, Damala K, Tsanou E, Michael MM, Malamou-Mitsi V, Stavropoulos NE: Thrombospondin-1 expression in Urothelial carcinoma: prognostic significance and association with p53 alerations, tumour angiogenesis, and extracellular matrix components. BMC Cancer 2006, 6:140. CrossRef
- Michaelis M, Michaelis R, Fleming I, Suhan T, Cinatl J, Blaheta RA, Hoffman K, Kotchetkov R, Busse R, Nau H, Cinatl J: Valproic Acid inhibits angiogenesis in vitro and in vivo. Mol Pharmacol 2004, 65:520–527. CrossRef
- Lexi-Comp Inc. (Lexi-Drugs™) Lexi-Comp, Inc; June 1, 2012.
- Kwiecinska P, Tauboll E, Gregoraszczuk EL: Effects of valproic acid and levetiracetam on viability and cell cycle regulatory genes expression in the OVCAR-3 cell line. Pharmacol Rep 2012, 64:157–165.
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2490/12/21/prepub
- Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
- Online Date
- August 2012
- Online ISSN
- BioMed Central
- Additional Links
- Bladder cancer
- Valproic acid
- Thrombospondin-1, Urothelial carcinoma
- Gene expression
- Author Affiliations
- 1. Department of Urology, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY, 13210, USA
- 2. Department of Obstetrics and Gynecology, University of Rochester, 601 Elmwood Avenue, Rochester, NY, 14642, USA
- 3. Department of Urology, University of Rochester, 601 Elmwood Avenue, Rochester, NY, 14642, USA