Magnesium Valproate Inhibits Transitional Cell Carcinoma Of The Bladder: A Clinical Study

Background:Histone acetylation as an epigenetic change is widely studied in cancer. An imbalance in histone acetylation can lead to changes in chromatin structure and transcriptional dysregulation of genes that control over proliferation, cell-cycle progression, differentiation and apoptosis. Valproate acid, a histone deacetylases inhibitor, has been verificated to have anticancer effects in many studies. The purpose of this study is to explore the efficacy and safety of magnesium valproate treatment to bladder tumor.Methods:Twenty-four patients diagnosed with bladder tumor by biopsy under cystoscopy were administered magnesium valproate at 20mg/kg·d or 30mg/kg·d dose level(12 patients each, randomly) via oral route for 10 days before conventional surgical intervention. The tumor tissues and blood sample from baseline and posttreatment were collected (The surgical tumor tissues from additional 24 patients without magnesium valproate treatment were collected as control group of acetylation assay). The anticancer activity including tumor acetylation of H3 histones by detecting OD value (between magnesium valproate treatment group and control group), inhibition of VEGF expression by immunohistochemistry and induction of apoptosis by TUNEL (between baseline tumor biopsies and surgical tumor tissues).were evaluated according to the study protocol. Blood serum VPA concentrations were measured in all 24 patients. Besides, side effects of treatment were observed. ResuLts:All patients received the medication without dosage adjustment. The mean daily dose for the doses 20-and 30-mg/kg were 1220,1890 mg, respectively. Serum levels of valproic acid ranged from 77.4-137.3μg/mL, for a overall mean of 106.5μg/mL, and corresponding average blood levels for the two doses were 96.51,116.53μg/mL. The most frequent complaints were moderate somnolence (3 patients) and slight fatigue (4 patients), but no severe toxicity was reported. Our study showed H3 histone acetylation level in tumors after magnesium valproate treatment (regardless of dose level) is higher than that of control group(p=0.001), especially for invasive bladder tumor (p＜0.001). At 30-mg/kg dose level, histone H3 acetylation in tumors after magnesium valproate treatment is higher than that of control group (p=0.001). Whereas, the difference was no statistically significant between 20-mg/kg dose level magnesium valproate treatment group and control group (p=0.098). There were inhibition of VEGF expression for invasive bladder tumor, in 4 of 11patients (36.4%), and 3 of the four cases belonged to the 30 mg/kg dose level. Besides, for 11 patients with invasive bladder tumor, the apoptotic index mean of post-treatment samples was significantly higher than that of pre-treatment samples (p=0.008). Six cases treated by 30mg/kg·d magnesium valproate had significantly higher AI than their initial counterparts (p<0.05).Conclusion:Magnesium valproate at 30 mg/kg dose level acetylates H3 histones in bladder tumor tissues, inhibits expression of VEGF, induces apoptosis in tumor, and is well-tolerated.