Cytotoxic Activity of Valproic Acid on Primary Chronic Lymphocytic Leukemia Cells

Abstract

Background. Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in western civilization. The accumulation of CD5 + CD19 + B lymphocytes in peripheral blood is due to a defect in the apoptotic pathway rather than excessive proliferation in the bone marrow and lymph nodes. Despite a number of treatments, CLL remains an incurable disease. Valproic acid (VPA) activity, as a histone deacetylase inhibitor, could restore the epigenetic changes underlying the pathogenesis of CLL and thus induce cell death. Objectives. In the present study we hypothesized that VPA could induce CLL primary cells death through activation of apoptosis. Material and Methods. Peripheral blood samples were obtained from 53 CLL patients. Peripheral blood mononuclear cells were isolated through density gradient centrifugation and were the subject of a 24-hour cell culture with 10 mM of VPA. The cytotoxic effect of VPA was evaluated with an XTT test and thereafter confirmed using Annexin V-FITC/PI staining and flow cytometry techniques. Results. In this study, a median VPA cytotoxicity of 13.88% with a range of 0-54.65% was observed. Annexin V/PI staining confirmed that the demonstrated cytotoxicity was caused by increased apoptosis in the VPA treated cells as compared to control cells. Statistical analysis showed that VPA's effect on CLL cells depends on lactate dehydrogenase serum levels, but is independent of all other prognostic markers. Conclusions. The results of the present experiments found that VPA at a clinically applicable concentration significantly induces apoptosis independently of the disease stage and might be a valuable therapeutic agent for all CLL patients (Adv Clin Exp Med 2015, 24, 1, 55-62).

Proliferation and apoptosis of T lymphocytes in patients with bipolar disorder

“…Several studies have shown the effect of lithium on cytokine production by monocytes in breast cancer patients 15 – 17 . Meanwhile, valproic acid is mainly known for its antileukemic properties; it induces apoptosis of chronic lymphocytic leukemia cells 18 , 19 .…”

Relationship between the expression of CD25 and CD69 on the surface of lymphocytes T and B from peripheral blood and bone marrow of patients with chronic lymphocytic leukemia and established prognostic factors of this disease

“…Lymphocyte doubling time longer than 12 months is usually associated with a mild course of CLL; however, the shorter the LDT, the more aggressive is the phenotype of the disease. [6][7][8][9] The concentration of beta-2 microglobulin is another established prognostic factor: the higher the value of this parameter, the worse is the prognosis. 10 Chronic lymphocytic leukemia cells differ in terms of the mutational status of genes encoding immunoglobulin heavy chain variable (IgVH), which is correlated with the intracellular expression of ζ-associated protein-70 (ZAP-70), the presence of the CD38 antigen and the degree of activation and susceptibility to apoptosis.…”

Valproic acid combined with cisplatin-based chemoradiation in locally advanced head and neck squamous cell carcinoma patients and associated biomarkers

“…Patients submitted to CCRT and VPA experienced a higher rate of medullary toxicity and infection than reported in the literature and historical control data from our institution [29]. A possible synergistic effect of VPA and CCRT in the observed lymphopenia might have occurred, leading to the exacerbated toxicity in this trial [38,39]. Somnolence was frequent, however, manageable and there was no apparent compromise in quality of life.…”