Abstract
Temozolomide (TMZ) has become a key therapeutic agent in patients with malignant gliomas; however, its survival benefit remains unsatisfactory. Valproic acid (VPA) has emerged as an anticancer drug via inhibition of histone deacetylases (HDACs), but the therapeutic advantages of a combination with VPA and TMZ remain poorly understood. The main aim of the present study was to determine whether an antitumor effect could be potentiated by a combination of VPA and TMZ, especially in TMZ-resistant cell lines. A combination of VPA and TMZ had a significantly enhanced antitumor effect in TMZ-resistant malignant glioma cells (T98 and U138). This enhanced antitumor effect correlated with VPA-mediated reduced O6-methylguanine-DNA methyltransferase (MGMT) expression, which plays an important role in cellular resistance to alkylating agents. In vitro, the combination of these drugs enhanced the apoptotic and autophagic cell death, as well as suppressed the migratory activities in TMZ-resistant cell lines. Furthermore, in vivo efficacy experiment showed that treatment of combination of VPA and TMZ significantly inhibited tumor growth compared with the monotherapy groups of mice. These results suggest that the clinical efficacy of TMZ chemotherapy in TMZ-resistant malignant glioma may be improved by combination with VPA.
Highlights
Malignant gliomas are the most common primary tumors of the central nervous system
A trial of concomitant and adjuvant TMZ in addition to radiotherapy for new glioblastomas demonstrated an increase in median survival from 12.1 to 14.6 months and an increase in the 2-year survival rate from 10 to 26% compared with radiotherapy alone [2]
A significant enhanced antitumor effect of the combined treatment of Valproic acid (VPA) and TMZ was observed in T98 (P = 0.034, combination treatment versus single treatment) and U138 cells (P = 0.042, combination treatment versus single treatment; Figure 2(b)). These results suggest that the combination of VPA with TMZ has combined or enhanced antitumor effects in the malignant glioma cell lines
Summary
Malignant gliomas are the most common primary tumors of the central nervous system. multimodality treatments exist, including extensive tumor resection, radiation therapy, and chemotherapy, their prognosis is poor. The alkylating agent temozolomide (3,4-dihydro-3-methyl-4oxoimidazo-[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, TMZ) has received much attention as a treatment for malignant gliomas [1]. Recent studies have indicated that the resistance to TMZ observed in malignant gliomas is related to the DNA repair enzyme, O6methylguanine-DNA methyltransferase (MGMT), leading to the replication of DNA and the growth of tumors [3,4,5,6]. Valproic acid (VPA) is an approved drug for the treatment of epileptic seizures, bipolar disorders, and migraine and acts via inhibition of the transamination of gammaaminobutyric acid. VPA is a short-chain fatty acid that inhibits histone deacetylases (HDACs) [7,8,9]. VPA has been examined as an HDAC inhibitor (HDACI) in Journal of Biomedicine and Biotechnology numerous preclinical and clinical trials for solid tumors and leukemias [12, 13]
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