Valproic acid downregulates the expression of MGMT and sensitizes temozolomide-resistant glioma cells.
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.
Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seocho-gu, Seoul 137-701, Republic of Korea.
Chung Heon
CH
Ryu
Wan Soo
WS
Yoon
Kwang Ywel
KY
Park
Seong Muk
SM
Kim
Jung Yeon
JY
Lim
Ji Sun
JS
Woo
Chang Hyun
CH
Jeong
Yun
Y
Hou
Sin-Soo
SS
Jeun
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000096:biosynthesis / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000235:genetics*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D051379:Mice; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics*; D014635:Valproic Acid / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D025521:Tumor Suppressor Proteins; D014635:Valproic Acid; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide