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

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.Bladder cancer is the fourth most commonly diagnosed cancer in the United States with over 60,000 new cases per year [1]. Fortunately, the majority of these cancers are superficial and successfully treated surgically. Unfortunately, these patients require intense follow-up due to high recurrence rates and the potential for progression to invasive cancer. Cystoscopy is recommended at regular intervals and even the lowest risk patients have a 30% recurrence rate at 5？years [2]. This constant need for surveillance imposes economic and life style hardship. An effective therapy to decrease bladder cancer recurrence could have significant impact on both quality of life and survival for over 500,000 patients with a history of bladder cancer in the United States alone.Post-translational histone modifications such as acetylation are associated with transcriptionally active regions of the genome. Histone deacetylation appears to be a mechanism whereby cancers decrease expression of genes involved in cell cycle control and apoptosis. Histone deacetylase inhibitors (HDACi) are an emerging class of cancer drugs that might be useful in preventing bladder cancer recurrence. Valproic acid (sodium valproate) is a relatively weak HDACi but has demonstrated potential in the treatment of glioblastomas [3], thyroid cancer [4], and leukemia [5]. There are several on-going