Animals; Antineoplastic Agents/adverse effects/pharmacology/therapeutic use; Brain Neoplasms/drug therapy/pathology; Clinical Trials as Topic; Combined Modality Therapy; DNA Repair/drug effects; Drug Evaluation, Preclinical; Glioblastoma/drug therapy/pathology; Glioma/drug therapy/pathology; Humans; Valproic Acid/adverse effects/pharmacology/therapeutic use
Abstract :
[en] INTRODUCTION: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to inhibit the proliferation of various cancers including glioblastoma multiforme. AREAS COVERED: We provide a comprehensive review of the mechanisms of action of valproate in gliomas, of its potential side effects and of the published clinical results obtained with this drug in glioblastomas. Valproate inhibits a subset of histone deacetylases and cellular kinases, and affects gene transcription through histone hyperacetylation, DNA hypomethylation and the modulation of several transcription factors. As a result, VPA induces differentiation of glioma cells, can prevent their invasion in surrounding tissues and may inhibit tumor angiogenesis. VPA can also inhibit DNA repair, thereby potentiating cytotoxic treatments such as chemotherapies or radiation therapy. Based on these mechanisms and case reports of glioblastoma remissions following VPA treatment, several clinical studies currently assess the therapeutic potential of VPA in glioma therapy. EXPERT OPINION: The combination of VPA treatment with chemotherapy and radiotherapy in glioblastoma appears a rational option that deserves well-designed prospective clinical trials that assess the efficacy and the molecular characteristics of the responding tumors in these patients.
Disciplines :
Genetics & genetic processes
Author, co-author :
Berendsen, Sharon
Broekman, Marike
Seute, Tatjana
Snijders, Tom
van Es, Corine
de Vos, Filip
Regli, Luca
Robe, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Language :
English
Title :
Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results.
Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, et al. Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors. Cancer Treat Rev 2008;34(3):206-22
Perucca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs 2002;16(10):695-714. (Pubitemid 35176854)
Gottlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 2001;20(24):6969-78 (Pubitemid 34062289)
Bradner JE, Mak R, Tanguturi SK, et al. Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease. Proc Natl Acad Sci USA 2010;107(28):12617-22.
Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet 2009;10(1):32-42
Chen Y, Wang H, Yoon SO, et al. HDAC-mediated deacetylation of NF-kappaB is critical for schwann cell myelination. Nat Neurosci 2011;14(4):437-41.
Yuan ZL, Guan YJ, Chatterjee D, Chin YE. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 2005;307(5707):269-73 (Pubitemid 40116244)
Buerki C, Rothgiesser KM, Valovka T, et al. Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65. Nucleic Acids Res 2008;36(5):1665-80 (Pubitemid 351426117)
Chen CS, Weng SC, Tseng PH, et al. Histone acetylation-independent effect of histone deacetylase inhibitors on akt through the reshuffling of protein phosphatase 1 complexes. J Biol Chem 2005;280(46):38879-87
Togi S, Kamitani S, Kawakami S, et al. HDAC3 influences phosphorylation of STAT3 at serine 727 by interacting with PP2A. Biochem Biophys Res Commun 2009;379(2):616-20
Wagner JM, Hackanson B, Lubbert M, Jung M. Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin Epigenetics 2010;1(3-4):117-36
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987-96. (Pubitemid 40349501)
Nagarajan RP, Costello JF. Epigenetic mechanisms in glioblastoma multiforme. Semin Cancer Biol 2009;19(3):188-97
Bredel M, Scholtens DM, Yadav AK, et al. NFKBIA deletion in glioblastomas. N Engl J Med 2011;364(7):627-37
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455(7216):1061-8
Campos B, Bermejo JL, Han L, et al. Expression of nuclear receptor corepressors and class I histone deacetylases in astrocytic gliomas. Cancer Sci 2011;102(2):387-92
Sharma V, Koul N, Joseph C, et al. HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity. J Cell Mol Med 2010;14(8):2151-61
Gensert JM, Baranova OV, Weinstein DE, Ratan RR. CD81, a cell cycle regulator, is a novel target for histone deacetylase inhibition in glioma cells. Neurobiol Dis 2007;26(3):671-80 (Pubitemid 46756332)
Sarcar B, Kahali S, Chinnaiyan P. Vorinostat enhances the cytotoxic effects of the topoisomerase I inhibitor SN38 in glioblastoma cell lines. J Neurooncol 2010;99(2):201-7
Chinnaiyan P, Vallabhaneni G, Armstrong E, et al. Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 2005;62(1):223-9 (Pubitemid 40591946)
Robe PA, Jolois O, N'Guyen M, et al. Modulation of the HSV-TK/ganciclovir bystander effect by n-butyrate in glioblastoma: correlation with gap-junction intercellular communication. Int J Oncol 2004;25(1):187-92
Su JM, Li XN, Thompson P, et al. Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: a children's oncology group report. Clin Cancer Res 2011;17(3):589-97
Eot-Houllier G, Fulcrand G, Magnaghi-Jaulin L, Jaulin C. Histone deacetylase inhibitors and genomic instability. Cancer Lett 2009;274(2):169-76
Bertrand P. Inside HDAC with HDAC inhibitors. Eur J Med Chem 2010;45(6):2095-116
Marchion DC, Bicaku E, Turner JG, et al. HDAC2 regulates chromatin plasticity and enhances DNA vulnerability. Mol Cancer Ther 2009;8(4):794-801
Chen X, Wong P, Radany E, Wong JY. HDAC inhibitor, valproic acid, induces p53-dependent radiosensitization of colon cancer cells. Cancer Biother Radiopharm 2009;24(6):689-99
Lucio-Eterovic AK, Cortez MA, Valera ET, et al. Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue: class II and IV are hypoexpressed in glioblastomas. BMC Cancer 2008;8:243
Mehnert JM, Kelly WK. Histone deacetylase inhibitors: biology and mechanism of action. Cancer J 2007;13(1):23-9
Hayakawa T, Nakayama J. Physiological roles of class I HDAC complex and histone demethylase. J Biomed Biotechnol 2011;2011:129383
Campbell KJ, Rocha S, Perkins ND. Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol Cell 2004;13(6):853-65 (Pubitemid 38438480)
Bhat KP, Pelloski CE, Zhang Y, et al. Selective repression of YKL-40 by NF-kappaB in glioma cell lines involves recruitment of histone deacetylase-1 and -2. FEBS Lett 2008;582(21-22):3193-200
Burton TR, Eisenstat DD, Gibson SB. BNIP3 (bcl-2 19 kDa interacting protein) acts as transcriptional repressor of apoptosis-inducing factor expression preventing cell death in human malignant gliomas. J Neurosci 2009;29(13):4189-99
Sadoul K, Wang J, Diagouraga B, Khochbin S. The tale of protein lysine acetylation in the cytoplasm. J Biomed Biotechnol 2011;2011:970382
Choudhary C, Kumar C, Gnad F, et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009;325(5942):834-40
Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone proteins. Gene 2005;363:15-23. (Pubitemid 41691888)
Li L, Gondi CS, Dinh DH, et al. Transfection with anti-p65 intrabody suppresses invasion and angiogenesis in glioma cells by blocking nuclear factor-kappaB transcriptional activity. Clin Cancer Res 2007;13(7):2178-90 (Pubitemid 46649888)
Kiernan R, Bres V, Ng RW, et al. Post-activation turn-off of NF-kappa Bdependent transcription is regulated by acetylation of p65. J Biol Chem 2003;278(4):2758-66 (Pubitemid 36801357)
Liu BL, Cheng JX, Zhang X, et al. Global histone modification patterns as prognostic markers to classify glioma patients. Cancer Epidemiol Biomarkers Prev 2010;19(11):2888-96
Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science 2008;321(5897):1807-12
Chang CJ, Hsu CC, Yung MC, et al. Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression. Biochem Biophys Res Commun 2009;380(2):236-42
Inoue T, Hiratsuka M, Osaki M, et al. SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. Oncogene 2007;26(7):945-57
Kito M, Maehara M, Watanabe K. Antiepileptic drugs-calcium current interaction in cultured human neuroblastoma cells. Seizure 1994;3(2):141-9 (Pubitemid 24186083)
Johannessen CU. Mechanisms of action of valproate: a commentatory. Neurochem Int 2000;37(2-3):103-10 (Pubitemid 30254142)
Jung GA, Yoon JY, Moon BS, et al. Valproic acid induces differentiation and inhibition of proliferation in neural progenitor cells via the beta-catenin-ras- ERK-p21Cip/WAF1 pathway. BMC Cell Biol 2008;9:66
Chen G, Huang LD, Jiang YM, Manji HK. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem 1999;72(3):1327-30 (Pubitemid 29085050)
Bermudez-Lugo JA, Perez-Gonzalez O, Rosales-Hernandez MC, et al. Exploration of the valproic acid binding site on histone deacetylase 8 using docking and molecular dynamic simulations. J Mol Model 2011. [Epub ahead of print]
Phiel CJ, Zhang F, Huang EY, et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 2001;276(39):36734-41
Khan N, Jeffers M, Kumar S, et al. Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors. Biochem J 2008;409(2):581-9 (Pubitemid 351184977)
Gurvich N, Tsygankova OM, Meinkoth JL, Klein PS. Histone deacetylase is a target of valproic acid-mediated cellular differentiation. Cancer Res 2004;64(3):1079-86 (Pubitemid 38176913)
Bradbury CA, Khanim FL, Hayden R, et al. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 2005;19(10):1751-9 (Pubitemid 41486152)
Benitez JA, Arregui L, Cabrera G, Segovia J. Valproic acid induces polarization, neuronal-like differentiation of a subpopulation of C6 glioma cells and selectively regulates transgene expression. Neuroscience 2008;156(4):911-20
Das CM, Aguilera D, Vasquez H, et al. Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. J Neurooncol 2007;85(2):159-70 (Pubitemid 47629397)
Camphausen K, Cerna D, Scott T, et al. Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. Int J Cancer 2005;114(3):380-6. (Pubitemid 40279957)
Condorelli F, Gnemmi I, Vallario A, et al. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br J Pharmacol 2008;153(4):657-68 (Pubitemid 351271755)
Galanis E, Jaeckle KA, Maurer MJ, et al. Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol 2009;27(12):2052-8
Iwamoto FM, Lamborn KR, Kuhn JG, et al. A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: north american brain tumor consortium study 03-03. Neuro Oncol 2011;13(5):509-16
Wu SC, Zhang Y. Active DNA demethylation: many roads lead to rome. Nat Rev Mol Cell Biol 2010;11(9):607-20
Rajendran G, Shanmuganandam K, Bendre A, et al. Epigenetic regulation of DNA methyltransferases: DNMT1 and DNMT3B in gliomas. J Neuro Oncology 2011;104(2):483-94
Foltz G, Yoon JG, Lee H, et al. DNA methyltransferase-mediated transcriptional silencing in malignant glioma: a combined whole-genome microarray and promoter array analysis. Oncogene 2009;28(29):2667-77
Perisic T, Zimmermann N, Kirmeier T, et al. Valproate and amitriptyline exert common and divergent influences on global and gene promoter-specific chromatin modifications in rat primary astrocytes. Neuropsychopharmacology 2010;35(3):792-805
Milutinovic S, D'Alessio AC, Detich N, Szyf M. Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis 2007;28(3):560-71 (Pubitemid 46523352)
Papi A, Ferreri AM, Rocchi P, et al. Epigenetic modifiers as anticancer drugs: effectiveness of valproic acid in neural crest-derived tumor cells. Anticancer Res 2010;30(2):535-40
Sasai K, Akagi T, Aoyanagi E, et al. O6-methylguanine-DNA methyltransferase is downregulated in transformed astrocyte cells: implications for anti-glioma therapies. Mol Cancer 2007;6:36
Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352(10):997-1003 (Pubitemid 40349502)
Bosetti F, Bell JM, Manickam P. Microarray analysis of rat brain gene expression after chronic administration of sodium valproate. Brain Res Bull 2005;65(4):331-8 (Pubitemid 41057803)
Li B, Zhang S, Li M, et al. Down-regulation of GluK2 kainate receptor expression by chronic treatment with mood-stabilizing anti-convulsants or lithium in cultured astrocytes and brain, but not in neurons. Neuropharmacology 2009;57(4):375-85
Stamatopoulos B, Meuleman N, De Bruyn C, et al. Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis. Leukemia 2009;23(12):2281-9
De la Cruz-Hernandez E, Perez-Plasencia C, Perez-Cardenas E, et al. Transcriptional changes induced by epigenetic therapy with hydralazine and magnesium valproate in cervical carcinoma. Oncol Rep 2011;25(2):399-407
Frattola L, Ferrarese C, Canal N, et al. Characterization of the gamma-aminobutyric acid receptor system in human brain gliomas. Cancer Res 1985;45(9):4495-8 (Pubitemid 16224920)
Roach JD Jr, Aguinaldo GT, Jonnalagadda K, et al. Gamma-aminobutyric acid inhibits synergistic interleukin-6 release but not transcriptional activation in astrocytoma cells. Neuroimmunomodulation 2008;15(2):117-24
Liu Q, Li G, Li R, et al. IL-6 promotion of glioblastoma cell invasion and angiogenesis in U251 and T98G cell lines. J Neurooncol 2010;100(2):165-76
Thompson CB. Metabolic enzymes as oncogenes or tumor suppressors. N Engl J Med 2009;360(8):813-15
Latour I, Louw DF, Beedle AM, et al. Expression of T-type calcium channel splice variants in human glioma. Glia 2004;48(2):112-19 (Pubitemid 39545943)
Lu F, Chen H, Zhou C, Wu S. Is there a role for T-type Ca2+ channel in glioma cell proliferation? Cell Calcium 2005;38(6):593; 5; author reply 597
Panner A, Cribbs LL, Zainelli GM, et al. Variation of T-type calcium channel protein expression affects cell division of cultured tumor cells. Cell Calcium 2005;37(2):105-19 (Pubitemid 40017369)
Bertolesi GE, Shi C, Elbaum L, et al. The ca(2+) channel antagonists mibefradil and pimozide inhibit cell growth via different cytotoxic mechanisms. Mol Pharmacol 2002;62(2):210-19 (Pubitemid 34804099)
Wang Z, Xu L, Zhu X, et al. Demethylation of specific Wnt/betacatenin pathway genes and its upregulation in rat brain induced by prenatal valproate exposure. Anat Rec (Hoboken) 2010;293(11):1947-53
Zhang X, Chen T, Zhang J, et al. Notch1 promotes glioma cell migration and invasion by stimulating beta-catenin and NF-kappaB signaling via AKT activation. Cancer Sci 2012;103(2):181-90
Williams SP, Nowicki MO, Liu F, et al. Indirubins decrease glioma invasion by blocking migratory phenotypes in both the tumor and stromal endothelial cell compartments. Cancer Res 2011;71(16):5374-80
Bowman A, Nusse R. Location, location, location: foxM1 mediates beta-catenin nuclear translocation and promotes glioma tumorigenesis. Cancer Cell 2011;20(4):415-16
Kim Y, Kim KH, Lee J, et al. Wnt activation is implicated in glioblastoma radioresistance. Lab Invest 2012;92(3):466-73
Kotliarova S, Pastorino S, Kovell LC, et al. Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation. Cancer Res 2008;68(16):6643-51
Korur S, Huber RM, Sivasankaran B, et al. GSK3beta regulates differentiation and growth arrest in glioblastoma. PLoS One 2009;4(10):e7443
Miyashita K, Kawakami K, Nakada M, et al. Potential therapeutic effect of glycogen synthase kinase 3beta inhibition against human glioblastoma. Clin Cancer Res 2009;15(3):887-97
Knupfer MM, Hernaiz-Driever P, Poppenborg H, et al. Valproic acid inhibits proliferation and changes expression of CD44 and CD56 of malignant glioma cells in vitro. Anticancer Res 1998;18(5A):3585-9 (Pubitemid 28546494)
Chinnaiyan P, Cerna D, Burgan WE, et al. Postradiation sensitization of the histone deacetylase inhibitor valproic acid. Clin Cancer Res 2008;14(17):5410-15
Fu J, Shao CJ, Chen FR, et al. Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines. Neuro Oncol 2010;12(4):328-40
Chen CH, Chang YJ, Ku MS, et al. Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation. J Mol Med 2011;89(3):303-15
Bacon CL, Gallagher HC, Haughey JC, Regan CM. Antiproliferative action of valproate is associated with aberrant expression and nuclear translocation of cyclin D3 during the C6 glioma G1 phase. J Neurochem 2002;83(1):12-19
Fortson WS, Kayarthodi S, Fujimura Y, et al. Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells. Int J Oncol 2011;39(1):111-19
Simboeck E, Sawicka A, Zupkovitz G, et al. A phosphorylation switch regulates the transcriptional activation of cell cycle regulator p21 by histone deacetylase inhibitors. J Biol Chem 2010;285(52):41062-73
Dash BC, El-Deiry WS. Phosphorylation of p21 in G2/M promotes cyclin B-Cdc2 kinase activity. Mol Cell Biol 2005;25(8):3364-87 (Pubitemid 40464336)
Ando T, Kawabe T, Ohara H, et al. Involvement of the interaction between p21 and proliferating cell nuclear antigen for the maintenance of G2/M arrest after DNA damage. J Biol Chem 2001;276(46):42971-7
Ichiyama T, Okada K, Lipton JM, et al. Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB. Brain Res 2000;857(1-2):246-51 (Pubitemid 30107811)
Lehmann A, Denkert C, Budczies J, et al. High class I HDAC activity and expression are associated with RelA/ p65 activation in pancreatic cancer in vitro and in vivo. BMC Cancer 2009;9:395
Rao JS, Bazinet RP, Rapoport SI, Lee HJ. Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-kappaB DNA binding activity and COX-2 mRNA. Bipolar Disord 2007;9(5):513-20. (Pubitemid 47202514)
de la Iglesia N, Konopka G, Puram SV, et al. Identification of a PTEN-regulated STAT3 brain tumor suppressor pathway. Genes Dev 2008;22(4):449-62 (Pubitemid 351272753)
Chen Q, Ouyang DY, Geng M, et al. Valproic acid exhibits biphasic effects on apoptotic cell death of activated lymphocytes through differential modulation of multiple signaling pathways. J Immunotoxicol 2011;8(3):210-18
Liang QC, Xiong H, Zhao ZW, et al. Inhibition of transcription factor STAT5b suppresses proliferation, induces G1 cell cycle arrest and reduces tumor cell invasion in human glioblastoma multiforme cells. Cancer Lett 2009;273(1):164-71
Hu J, Jo M, Cavenee WK, et al. Crosstalk between the urokinase-type plasminogen activator receptor and EGF receptor variant III supports survival and growth of glioblastoma cells. Proc Natl Acad Sci USA 2011;108(38):15984-9
Alvarez-Breckenridge CA, Yu J, Price R, et al. The HDAC inhibitor valproic acid lessens NK cell action against oncolytic virus-infected glioblastoma cells with inhibition of STAT5/T-BET signaling and IFNgamma generation. J Virol 2012;86(8):4566-77
Gotfryd K, Skladchikova G, Lepekhin EA, et al. Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation. BMC Cancer 2010;10:383
Lange C, Mix E, Frahm J, et al. Small molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells. Neurosci Lett 2011;488(1):36-40
Jonathan Ryves W, Dalton EC, Harwood AJ, Williams RS. GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid. Bipolar Disord 2005;7(3):260-5 (Pubitemid 40778888)
Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 2006;9(3):157-73 (Pubitemid 43357943)
Wolff JE, Kramm C, Kortmann RD, et al. Valproic acid was well tolerated in heavily pretreated pediatric patients with high-grade glioma. J Neurooncol 2008;90(3):309-14
Morita K, Gotohda T, Arimochi H, et al. Histone deacetylase inhibitors promote neurosteroid-mediated cell differentiation and enhance serotonin-stimulated brain-derived neurotrophic factor gene expression in rat C6 glioma cells. J Neurosci Res 2009;87(11):2608-14
Tabu K, Sasai K, Kimura T, et al. Promoter hypomethylation regulates CD133 expression in human gliomas. Cell Res 2008;18(10):1037-46
Yagi Y, Fushida S, Harada S, et al. Effects of valproic acid on the cell cycle and apoptosis through acetylation of histone and tubulin in a scirrhous gastric cancer cell line. J Exp Clin Cancer Res 2010;29:149
Iacomino G, Medici MC, Russo GL. Valproic acid sensitizes K562 erythroleukemia cells to TRAIL/ Apo2L-induced apoptosis. Anticancer Res 2008;28(2A):855-64 (Pubitemid 351578930)
Xie C, Edwards H, Xu X, et al. Mechanisms of synergistic antileukemic interactions between valproic acid and cytarabine in pediatric acute myeloid leukemia. Clin Cancer Res 2010;16(22):5499-51
Brazelle W, Kreahling JM, Gemmer J, et al. Histone deacetylase inhibitors downregulate checkpoint kinase 1 expression to induce cell death in non-small cell lung cancer cells. PLoS ONE 2010;5(12):e14335
Chai G, Li L, Zhou W, et al. HDAC inhibitors act with 5-aza-2'-deoxycytidine to inhibit cell proliferation by suppressing removal of incorporated abases in lung cancer cells. PLoS ONE 2008;3(6):e2445
Lee JH, Choy ML, Ngo L, et al. Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proc Natl Acad Sci USA 2010;107(33):14639-44
Ciusani E, Balzarotti M, Calatozzolo C, et al. Valproic acid increases the in vitro effects of nitrosureas on human glioma cell lines. Oncol Res 2007;16(10):453-63
Blaheta RA, Michaelis M, Driever PH, Cinatl J Jr. Evolving anticancer drug valproic acid: insights into the mechanism and clinical studies. Med Res Rev 2005;25(4):383-97 (Pubitemid 40946533)
Michaelis M, Michaelis UR, Fleming I, et al. Valproic acid inhibits angiogenesis in vitro and in vivo. Mol Pharmacol 2004;65(3):520-7 (Pubitemid 38264019)
Norden AD, Drappatz J, Wen PY. Antiangiogenic therapies for high-grade glioma. Nat Rev Neurol 2009;5(11):610-20
Zgouras D, Becker U, Loitsch S, Stein J. Modulation of angiogenesis-related protein synthesis by valproic acid. Biochem Biophys Res Commun 2004;316(3):693-7 (Pubitemid 38368008)
Gao D, Xia Q, Lv J, Zhang H. Chronic administration of valproic acid inhibits PC3 cell growth by suppressing tumor angiogenesis in vivo. Int J Urol 2007;14(9):838-45 (Pubitemid 47313269)
Osuka S, Takano S, Yamamoto T, et al. Histone deacetylase inhibitor, valproic acid inhibits glioma angiogenesis in vitro and in vivo in the brain. Neuro-oncol 2009;11(6):962
Kim SH, Jeong JW, Park JA, et al. Regulation of the HIF-1alpha stability by histone deacetylases. Oncol Rep 2007;17(3):647-51
Ellis L, Hammers H, Pili R. Targeting tumor angiogenesis with histone deacetylase inhibitors. Cancer Lett 2009;280(2):145-53
Kaur B, Khwaja FW, Severson EA, et al. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 2005;7(2):134-53 (Pubitemid 40590514)
Qiang L, Wu T, Zhang HW, et al. HIF-1alpha is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating notch signaling pathway. Cell Death Differ 2012;19(2):284-94
Lefranc F, Brotchi J, Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 2005;23(10):2411-22 (Pubitemid 46218735)
Zhai GG, Malhotra R, Delaney M, et al. Radiation enhances the invasive potential of primary glioblastoma cells via activation of the rho signaling pathway. J Neurooncol 2006;76(3):227-37
Kroonen J, Nassen J, Boulanger YG, et al. Human glioblastoma-initiating cells invade specifically the subventricular zones and olfactory bulbs of mice after striatal injection. Int J Cancer 2011;129(3):574-85
Teodorczyk M, Martin-Villalba A. Sensing invasion: cell surface receptors driving spreading of glioblastoma. J Cell Physiol 2010;222(1):1-10
Zamecnik J. The extracellular space and matrix of gliomas. Acta Neuropathol 2005;110(5):435-42 (Pubitemid 41672336)
An Z, Gluck CB, Choy ML, Kaufman LJ. Suberoylanilide hydroxamic acid limits migration and invasion of glioma cells in two and three dimensional culture. Cancer Lett 2010;292(2):215-27
Eyupoglu IY, Hahnen E, Trankle C, et al. Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275. Mol Cancer Ther 2006;5(5):1248-55 (Pubitemid 43881317)
Knupfer MM, Pulzer F, Schindler I, et al. Different effects of valproic acid on proliferation and migration of malignant glioma cells in vitro. Anticancer Res 2001;21(1A):347-51
Gilbertson RJ, Rich JN. Making a tumour's bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 2007;7(10):733-6 (Pubitemid 47463683)
Charles NA, Holland EC, Gilbertson R, et al. The brain tumor microenvironment. Glia 2011;59(8):1169-80
Markovic DS, Glass R, Synowitz M, et al. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J Neuropathol Exp Neurol 2005;64(9):754-62 (Pubitemid 41285807)
Chen FX, Ren WW, Yang Y, et al. Reciprocal effects of conditioned medium on cultured glioma cells and neural stem cells. J Clin Neurosci 2009;16(12):1619-23
Chirasani SR, Sternjak A, Wend P, et al. Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells. Brain 2010;133(Pt 7):1961-72
Chen PS, Wang CC, Bortner CD, et al. Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity. Neuroscience 2007;149(1):203-12 (Pubitemid 47488650)
Go HS, Seo JE, Kim KC, et al. Valproic acid inhibits neural progenitor cell death by activation of NF-kappaB signaling pathway and up-regulation of bcl-XL. J Biomed Sci 2011;18(1):48
Suh HS, Choi S, Khattar P, et al. Histone deacetylase inhibitors suppress the expression of inflammatory and innate immune response genes in human microglia and astrocytes. J Neuroimmune Pharmacol 2010;5(4):521-32
Baltes S, Fedrowitz M, Tortos CL, et al. Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays. J Pharmacol Exp Ther 2007;320(1):331-43 (Pubitemid 46025748)
Rivers F, O'Brien TJ, Callaghan R. Exploring the possible interaction between anti-epilepsy drugs and multidrug efflux pumps; in vitro observations. Eur J Pharmacol 2008;598(1-3):1-8
Tang R, Faussat AM, Majdak P, et al. Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1. Leukemia 2004;18(7):1246-51 (Pubitemid 39023135)
Kortenhorst MS, Zahurak M, Shabbeer S, et al. A multiple-loop, double-cube microarray design applied to prostate cancer cell lines with variable sensitivity to histone deacetylase inhibitors. Clin Cancer Res 2008;14(21):6886-94
Liu T, Liu PY, Tee AE, et al. Over-expression of clusterin is a resistance factor to the anti-cancer effect of histone deacetylase inhibitors. Eur J Cancer 2009;45(10):1846-54
Huang X, Guo B. Adenomatous polyposis coli determines sensitivity to histone deacetylase inhibitor-induced apoptosis in colon cancer cells. Cancer Res 2006;66(18):9245-51 (Pubitemid 44521146)
Fedier A, Dedes KJ, Imesch P, et al. The histone deacetylase inhibitors suberoylanilide hydroxamic (vorinostat) and valproic acid induce irreversible and MDR1-independent resistance in human colon cancer cells. Int J Oncol 2007;31(3):633-41
Imesch P, Dedes KJ, Furlato M, et al. MLH1 protects from resistance acquisition by the histone deacetylase inhibitor trichostatin A in colon tumor cells. Int J Oncol 2009;35(3):631-40
Cowell IG, Sunter NJ, Singh PB, et al. gammaH2AX foci form preferentially in euchromatin after ionising-radiation. PLoS ONE 2007;2(10):e1057
Goodarzi AA, Jeggo P, Lobrich M. The influence of heterochromatin on DNA double strand break repair: getting the strong, silent type to relax. DNA Repair (Amst) 2010;9(12):1273-82
Green SR, Choudhary AK, Fleming IN. Combination of sapacitabine and HDAC inhibitors stimulates cell death in AML and other tumour types. Br J Cancer 2010;103(9):1391-9
Sato A, Asano T, Horiguchi A, et al. Antitumor effect of suberoylanilide hydroxamic acid and topotecan in renal cancer cells. Oncol Res 2011;19(5):217-23
Stander M, Dichgans J, Weller M. Anticonvulsant drugs fail to modulate chemotherapy-induced cytotoxicity and growth inhibition of human malignant glioma cells. J Neurooncol 1998;37(3):191-8 (Pubitemid 28073691)
Camphausen K, Burgan W, Cerra M, et al. Enhanced radiation-induced cell killing and prolongation of gammaH2AX foci expression by the histone deacetylase inhibitor MS-275. Cancer Res 2004;64(1):316-21 (Pubitemid 38114113)
Puerto S, Ramirez MJ, Marcos R, et al. Radiation-induced chromosome aberrations in human euchromatic (17cen-p53) and heterochromatic (1cen- 1q12) regions. Mutagenesis 2001;16(4):291-6 (Pubitemid 32684777)
Pawlik TM, Keyomarsi K. Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys 2004;59(4):928-42 (Pubitemid 38834285)
Van Nifterik KA, Van den Berg J, Slotman BJ, et al. Valproic acid sensitizes human glioma cells for temozolomide and gamma-radiation. J Neurooncol 2012;107(1):61-7.
Camphausen K, Tofilon PJ. Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J Clin Oncol 2007;25(26):4051-6 (Pubitemid 47492949)
Thoms J, Bristow RG. DNA repair targeting and radiotherapy: a focus on the therapeutic ratio. Semin Radiat Oncol 2010;20(4):217-22
Mahaney BL, Meek K, Lees-Miller SP. Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem J 2009;417(3):639-50
Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell Res 2008;18(1):134-47
Shabason JE, Tofilon PJ, Camphausen K. Grand rounds at the national institutes of health: HDAC inhibitors as radiation modifiers, from bench to clinic. J Cell Mol Med 2011;15(12):2735-44
Kawano T, Akiyama M, Agawa-Ohta M, et al. Histone deacetylase inhibitors
Otsuki A, Patel A, Kasai K, et al. Histone deacetylase inhibitors augment antitumor efficacy of herpes-based oncolytic viruses. Mol Ther 2008;16(9):1546-55
Kothari V, Joshi G, Nama S, et al. HDAC inhibitor valproic acid enhances tumor cell kill in adenovirus-HSVtk mediated suicide gene therapy in HNSCC xenograft mouse model. Int J Cancer 2010;126(3):733-42
Hacker S, Dittrich A, Mohr A, et al. Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8. Oncogene 2009;28(35):3097-11
Balbi A, Sottofattori E, Mazzei M, Sannita WG. Study of bioequivalence of magnesium and sodium valproates. J Pharm Biomed Anal 1991;9(4):317-21
Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs-best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE commission on therapeutic strategies. Epilepsia 2008;49(7):1239-76 (Pubitemid 351991390)
Lundberg B, Nergardh A, Boreus LO. Plasma concentrations of valproate during maintenance therapy in epileptic children. J Neurol 1982;228(2):133-41 (Pubitemid 13240892)
Moody JP, Allan SM. Measurement of valproic acid in serum as the 4-bromophenacyl ester by high performance liquid chromatography. Clin Chim Acta 1983;127(2):263-9 (Pubitemid 13175334)
Tomson T, Dahl ML, Kimland E. Therapeutic monitoring of antiepileptic drugs for epilepsy. Cochrane Database Syst Rev 2007(1):CD002216
Covanis A, Gupta AK, Jeavons PM. Sodium valproate: monotherapy and polytherapy. Epilepsia 1982;23(6):693-72
Perrott J, Murphy NG, Zed PJ. L-carnitine for acute valproic acid overdose: a systematic review of published cases. Ann Pharmacother 2010;44(7-8):1287-93
Hagg S, Spigset O. Anticonvulsant use during lactation. Drug Saf 2000;22(6):425-40 (Pubitemid 30386461)
Wieser HG. Comparison of valproate concentrations in human plasma, CSF and brain tissue after administration of different formulations of valproate or valpromide. Epilepsy Res 1991;9(2):154-9
Fischer W, Praetor K, Metzner L, et al. Transport of valproate at intestinal epithelial (caco-2) and brain endothelial (RBE4) cells: mechanism and substrate specificity. Eur J Pharm Biopharm 2008;70(2):486-92
Froberg MK, Gerhart DZ, Enerson BE, et al. Expression of monocarboxylate transporter MCT1 in normal and neoplastic human CNS tissues. Neuroreport 2001;12(4):761-5 (Pubitemid 32222714)
Kiang TK, Ho PC, Anari MR, et al. Contribution of CYP2C9, CYP2A6, and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Toxicol Sci 2006;94(2):261-71 (Pubitemid 44817142)
Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003;2(6):347-56 (Pubitemid 38352562)
Yoon HW, Giraldo EA, Wijdicks EF. Valproic acid and warfarin: an underrecognized drug interaction. Neurocrit Care 2011;15(1):182-5
Pursche S, Schleyer E, von Bonin M, et al. Influence of enzyme-inducing antiepileptic drugs on trough level of imatinib in glioblastoma patients. Curr Clin Pharmacol 2008;3(3):198-20
Bourg V, Lebrun C, Chichmanian RM, et al. Nitroso-urea-cisplatin-based chemotherapy associated with valproate: increase of haematologic toxicity. Ann Oncol 2001;12(2):217-19 (Pubitemid 32223871)
Oberndorfer S, Piribauer M, Marosi C, et al. P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy. J Neurooncol 2005;72(3):255-60 (Pubitemid 40867409)
Yap KY, Chui WK, Chan A. Drug interactions between chemotherapeutic regimens and antiepileptics. Clin Ther 2008;30(8):1385-40
Atmaca A, Al-Batran SE, Maurer A, et al. Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial. Br J Cancer 2007;97(2):177-82 (Pubitemid 47057472)
Isojarvi JI, Laatikainen TJ, Pakarinen AJ, et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993;329(19):1383-8 (Pubitemid 23317348)
Verrotti A, D'Egidio C, Mohn A, et al. Antiepileptic drugs, sex hormones, and PCOS. Epilepsia 2011;52(2):199-21
Davis R, Peters DH, McTavish D. Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1994;47(2):332-72
Koenig S, Gerstner T, Keller A, et al. High incidence of vaproate-induced coagulation disorders in children receiving valproic acid: a prospective study. Blood Coagul Fibrinolysis 2008;19(5):375-82
Manohar C, Avitsian R, Lozano S, et al. The effect of antiepileptic drugs on coagulation and bleeding in the perioperative period of epilepsy surgery: the cleveland clinic experience. J Clin Neurosci 2011;18(9):1180-4
Anderson GD, Lin YX, Berge C, Ojemann GA. Absence of bleeding complications in patients undergoing cortical surgery while receiving valproate treatment. J Neurosurg 1997;87(2):252-6 (Pubitemid 27349110)
Psaras T, Will BE, Schoeber W, et al. Quantitative assessment of postoperative blood collection in brain tumor surgery under valproate medication. Zentralbl Neurochir 2008;69(4):165-9
Wolff JE, Driever PH, Erdlenbruch B, et al. Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol. Cancer 2010;116(3):705-12
Lehmann DF, Hurteau TE, Newman N, Coyle TE. Anticonvulsant usage is associated with an increased risk of procarbazine hypersensitivity reactions in patients with brain tumors. Clin Pharmacol Ther 1997;62(2):225-9 (Pubitemid 27373471)
Chapman SA, Wacksman GP, Patterson BD. Pancreatitis associated with valproic acid: a review of the literature. Pharmacotherapy 2001;21(12):1549-60 (Pubitemid 33117256)
Bohan TP, Helton E, McDonald I, et al. Effect of L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 2001;56(10):1405-9 (Pubitemid 32455310)
Samren EB, van Duijn CM, Koch S, et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint european prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1997;38(9):981-90 (Pubitemid 27382935)
Witt O, Schweigerer L, Driever PH, et al. Valproic acid treatment of glioblastoma multiforme in a child. Pediatr Blood Cancer 2004;43(2):181 (Pubitemid 38891170)
Rokes CA, Remke M, Guha-Thakurta N, et al. Sorafenib plus valproic acid for infant spinal glioblastoma. J Pediatr Hematol Oncol 2010;32(6):511-14
van Breemen MS, Rijsman RM, Taphoorn MJ, et al. Efficacy of anti-epileptic drugs in patients with gliomas and seizures. J Neurol 2009;256(9):1519-26
Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 2011;77(12):1156-64
Tsai HC, Wei KC, Tsai CN, et al. Effect of valproic acid on the outcome of glioblastoma multiforme. Br J Neurosurg 2011. [Epub ahead of print]
Ruben JD, Dally M, Bailey M, et al. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys 2006;65(2):499-50
Su JM, Li XN, Thompson P, et al. Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: a children's oncology group report. Clin Cancer Res 2011;17(3):589-97
Wolff JE, Boos J, Kuhl J. HIT-GBM: multicenter study of treatment of children with malignant glioma. Klin Padiatr 1996;208(4):193-6 (Pubitemid 26246750)
