Abstract
BackgroundThe development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest.MethodsTwelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each): 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period.ResultsAll patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6–170.49 μg/mL. Tumor deacetylase activity decreased in eight patients (80%), whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p < 0.0264). There was no correlation between H3 and H4 tumor hyperacetylation with serum levels of valproic acid.ConclusionMagnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.
Highlights
The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity
Previous studies have shown that histone acetylation can increase the efficiency of several anticancer drugs targeting the DNA [8,9,10,11]; studies shown that HDAC activity inhibitors enhance in vitro sensitivity of tumor cells to radiation [12,13,14]
Using the same scale for positive and negative control, we found that 8 of 12 (75%) patients had a decrease in deacetylase activity equal to or greater that observed in HeLa cell extracts treated or not with trichostatinA, whereas patients 3 and 8 (25%) had either no change or a mild increase in deacetylase activity
Summary
The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest. The development of cancer has been associated with epigenetic alterations such as deregulation of DNA methylation and aberrant histone deacetylase (HDAC) activity [1]. HDAC inhibition has been reported to induce tumor cell differentiation, apoptosis, or growth arrest, depending on the experimental system [4,5,6,7]. Previous studies have shown that histone acetylation can increase the efficiency of several anticancer drugs targeting the DNA [8,9,10,11]; studies shown that HDAC activity inhibitors enhance in vitro sensitivity of tumor cells to radiation [12,13,14]. A significant impediment in targeting HDAC has been lack of a clinically applicable HDAC inhibitor
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