Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study.
BACKGROUND
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.


METHODS
Twelve 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.


RESULTS
All 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 microg/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.


CONCLUSIONS
Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.
Chavez-Blanco
Alma
A
Unidad de Investigacion Biomedica en Cáncer, Instituto Nacional de Cancerología/Instituto de Investigaciones Biomédicas (INCan/IIB), Universidad Nacional Autonoma de Mexico, Mexico City, Mexico. celular_alma@hotmail.com
Segura-Pacheco
Blanca
B
Perez-Cardenas
Enrique
E
Taja-Chayeb
Lucia
L
Cetina
Lucely
L
Candelaria
Myrna
M
Cantu
David
D
Gonzalez-Fierro
Aurora
A
Garcia-Lopez
Patricia
P
Zambrano
Pilar
P
Perez-Plasencia
Carlos
C
Cabrera
Gustavo
G
Trejo-Becerril
Catalina
C
Angeles
Enrique
E
Duenas-Gonzalez
Alfonso
A
D000107:Acetylation; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008875:Middle Aged; D009367:Neoplasm Staging; D002583:Uterine Cervical Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014635:Valproic Acid / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use*
D006657:Histones; D014635:Valproic Acid; D006655:Histone Deacetylases