Top

Published in:

Open Access 01-12-2012 | Research article

Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression

Authors: Timothy K Byler, Dean Leocadio, Oleg Shapiro, Gennady Bratslavsky, Christopher J Stodgell, Ronald W Wood, Edward M Messing, Jay E Reeder

Published in: BMC Urology | Issue 1/2012

Abstract

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.

Available only for authorised users

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 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. 10.1016/j.eururo.2011.03.017.CrossRefPubMed

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. 10.1007/s11060-007-9402-7.CrossRefPubMed

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. 10.1677/joe.1.06970.CrossRefPubMed

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. 10.1182/blood-2007-03-078576.CrossRefPubMed

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. 10.1124/jpet.106.106658.CrossRefPubMed

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. 10.1016/j.canlet.2009.02.045.CrossRefPubMed

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. 10.1111/j.1464-410X.2009.08795.x.CrossRefPubMed

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.PubMed

10.

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.PubMed

11.

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. 10.1093/jnci/89.3.219.CrossRefPubMed

12.

Campbell SC, Bolpert OV, Ivanovich M, Bouck NP: Molecular mediators of angiogenesis in bladder cancer. Cancer Res. 1998, 58: 1298-1304.PubMed

13.

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: 7-10.1186/1471-2490-8-7.CrossRefPubMedPubMedCentral

14.

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.

15.

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. 10.1158/0008-5472.CAN-04-0496.CrossRefPubMed

16.

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

17.

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. 10.1006/meth.2001.1262.CrossRefPubMed

18.

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: 140-10.1186/1471-2407-6-140.CrossRefPubMedPubMedCentral

19.

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. 10.1124/mol.65.3.520.CrossRefPubMed

20.

Lexi-Comp Inc. (Lexi-Drugs™): June 1, 2012, Lexi-Comp, Inc

21.

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.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2490/12/21/prepub

Title: Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression
Authors: Timothy K Byler
Dean Leocadio
Oleg Shapiro
Gennady Bratslavsky
Christopher J Stodgell
Ronald W Wood
Edward M Messing
Jay E Reeder
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: BMC Urology / Issue 1/2012
Electronic ISSN: 1471-2490
DOI: https://doi.org/10.1186/1471-2490-12-21

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2012

Resistance profiles of urinary tract infections in general practice - an observational study

A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection

Laparoscopic and open postchemotherapy retroperitoneal lymph node dissection in patients with advanced testicular cancer – a single center analysis

Urinary levels of Hepatocarcinoma-intestine-pancreas/Pancreatitis-associated protein as a diagnostic biomarker in patients with bladder cancer

miR-21 may acts as an oncomir by targeting RECK, a matrix metalloproteinase regulator, in prostate cancer

Genetic variation in SPAG16 regions encoding the WD40 repeats is not associated with reduced sperm motility and axonemal defects in a population of infertile males