Histone deacetylase inhibitors valproate and trichostatin A are toxic to neuroblastoma cells and modulate cytochrome P450 1A1, 1B1 and 3A4 expression in these cells
Histone deacetylase inhibitors such as valproic acid (VPA) and trichostatin A (TSA) were shown to exert antitumor activity. Here, the toxicity of both drugs to human neuroblastoma cell lines was investigated using MTT test, and IC50 values for both compounds were determined. Another target of this work was to evaluate the effects of both drugs on expression of cytochrome P450 (CYP) 1A1, 1B1 and 3A4 enzymes, which are known to be expressed in neuroblastoma cells. A malignant subset of neuroblastoma cells, so-called N-type cells (UKF-NB-3 cells) and the more benign S-type neuroblastoma cells (UKF-NB-4 and SK-N-AS cell lines) were studied from both two points of view. VPA and TSA inhibited the growth of neuroblastoma cells in a dose-dependent manner. The IC50 values ranging from 1.0 to 2.8 mM and from 69.8 to 129.4 nM were found for VPA and TSA, respectively. Of the neuroblastoma tested here, the N-type UKF-NB-3 cell line was the most sensitive to both drugs. The different effects of VPA and TSA were found on expression of CYP1A1, 1B1 and 3A4 enzymes in individual neuroblastoma cells tested in the study. Protein expression of all these CYP enzymes in the S-type SK-N-AS cell line was not influenced by either of studied drugs. On the contrary, in another S-type cell line, UKF-NB-4, VPA and TSA induced expression of CYP1A1, depressed levels of CYP1B1 and had no effect on expression levels of CYP3A4 enzyme. In the N-type UKF-NB-3 cell line, the expression of CYP1A1 was strongly induced, while that of CYP1B1 depressed by VPA and TSA. VPA also induced the expression of CYP3A4 in this neuroblastoma cell line.
If the inline PDF is not rendering correctly, you can download the PDF file here.
Batty N Malouf GG Issa JP. (2009). Histone deacetylase inhibitors as anti-neoplastic agents. Cancer Lett280: 192-200.
Blaheta RA Cinatl J Jr. (2002). Anti-tumor mechanisms of valproate: a novel role for an old drug. Med Res Rev22: 492-511.
Bolden JE Peart MJ Johnstone RW. (2006). Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov5: 769-784.
Bort R Gomez-Lechon MJ Castell JV Jover R. (2004). Role of hepatocyte nuclear factor 3 gamma in the expression of human CYP2C genes. Arch Biochem Biophys426: 63-72.
Brodeur GM. (2003). Neuroblastoma: biological insights into a clinical enigma. Nat Rev Cancer3: 203-216.
Cerveny L Svecova L Anzenbacherova E Vrzal R Staud F Dvorak Z Ulrichova J Anzenbacher P Pavek P. (2007). Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. Drug Metab Dispos35: 1032-1041.
Cinatl J Jr. Cinatl J Scholz M Driever PH Henrich D Kabickova H Vogel JU Doerr HW Kornhuber B. (1996). Antitumor activity of sodium valproate in cultures of human neuroblastoma cells. Anticancer Drugs7: 766-773.
Condorelli F Gnemmi I Vallario A Genazzani AA Canonico PL. (2008). Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br J Pharmacol153: 657-668.
Duenas-Gonzalez A Candelaria M Perez-Plascencia C Perez-Cardenas E de la Cruz-Hernandez E Herrera LA. (2008). Valproic acid as epigenetic cancer drug: preclinical clinical and transcriptional effects on solid tumors. Cancer Treat Rev34: 206-222.
Fisher JE Nau H Löscher W. (1991). Alterations in the renal excretion of valproate and its metabolites after chronic treatment. Epilepsia32: 146-150.
Furchert SE Lanvers-Kaminsky C Juürgens H Jung M Loidl A Frühwald MC. (2007). Inhibitors of histone deacetylases as potential therapeutic tools for high-risk embryonal tumors of the nervous system of childhood. Int J Cancer120: 787-1794.
Hooven LA Mahadevan B Keshava C Johns C Pereira C Desai D Amin S Weston A Baird WM. (2005). Effects of suberoylanilide hydroxamic acid and trichostatin A on induction of cytochrome P450 enzymes and benzo[a]pyrene DNA adduct formation in human cells. Bioorg Med Chem Lett15: 1283-1287.
Hopkins-Donaldson S Yan P Bourloud KB Muhlethaler A Bodmer JL and Gross N. (2002). Doxorubicin-induced death in neuroblastoma does not involve death receptors in S-type cells and is caspase-independent in N-type cells. Oncogene21: 6132-6137.
Isojärvi JI Turkka J Pakarinen AJ Kotila M Rättyä J Myllylä VV. (2001). Thyroid function in men taking carbamazepine oxcarbazepine or valproate for epilepsy. Epilepsia42: 930-934.
Kiang TK Ho PC Anari MR Tong V Abbott FS Chang TK. (2006). Contribution of CYP2C9 CYP2A6 and CYP2B6 to valproic acid metabolism in hepatic microsomes from individuals with the CYP2C9*1/*1 genotype. Toxicol Sci94: 261-271.
Marchion DC Bicaku E Daud AI Sullivan DM Munster PN. (2005). Valproic acid alters chromatin structure by regulation of chromatin modulation proteins. Cancer Res65: 3815-3822.
Maris JM Mathay KK. (1999). Molecular biology of neuroblastomas. J Clin Oncol17: 2264-2279.
Marks PA Miller T Richon VM. (2003). Histone deacetylases. Curr Opin Pharmacol3: 344-351.
Marks PA Richon VM Miller T Kelly WK. (2004). Histone deacetylase inhibitors. Adv Cancer Res91: 137-168.
Michaelis M Doerr HW Cinatl J Jr. (2007). Valproic acid as anti-cancer drug. Curr Pharm Des13: 3378-3393.
Michaelis M Suhan T Cinatl J Driever PH Cinatl J Jr. (2004). Valproic acid and interferon-alpha synergistically inhibit neuroblastoma cell growth in vitro and in vivo. Int J Oncol25: 1795-1799.
Morgenstern BZ Krivoshik AP Rodriguez V and Anderson PM. (2004). Wilms' tumor and neuroblastoma. Acta Paediatr Suppl93: 78-85.
Myasoedova KN. (2008). New findings in studies of cytochromes P450. Biochemistry (Mosc)73: 965-969.
Nelson-DeGrave VL Wickenheisser JK Cockrell JE Wood JR Legro RS Strauss JF 3rd McAllister JM. (2004). Valproate potentiates androgen biosynthesis in human ovarian theca cells. Endocrinology145: 799-808.
Poljakova J Eckschlager T Hrabeta J Hrebackova J Smutny S Frei E Martinek V Kizek R Stiborova M. (2009). The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells. Biochem Pharmacol77: 1466-1479.
Rogiers V Akrawi M Vercruysse A Phillips IR Shephard EA. (1995). Effects of the anticonvulsant valproate on the expression of components of the cytochrome-P-450-mediated monooxygenase system and glutathione S-transferases. Eur J Biochem231: 337-343.
Rogiers V Callaerts A Vercruysse A Akrawi M Shephard E Phillips I. (1992). Effects of valproate on xenobiotic biotransformation in rat liver. In vivo and in vitro experiments. Pharm Weekbl Sci14: 127-131.
Santini V Gozzini A Ferrari G. (2007). Histone deacetylase inhibitors: molecular and biological activity as a premise to clinical application. Curr Drug Metab8: 383-393.
Servidei T Morosetti R Ferlini C Cusano G Scambia G Mastrangelo R Koeffler HP. (2004). The cellular response to PPARgamma ligands is related to the phenotype of neuroblastoma cell lines. Oncol Res14: 345-354.
Silva MF Aires CC Luis PB Ruiter JP Ijlst L Duran M Wanders RJ Tavares de Almeida I. (2008). Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review. J Inherit Metab Dis31: 205-216.
Snykers S Vanhaecke T De Becker A Papeleu P Vinken M Van Riet I Rogiers V. (2007). Chromatin remodeling agent trichostatin A: a key-factor in the hepatic differentiation of human mesenchymal stem cells derived of adult bone marrow. BMC Dev Biol7: 24-39.
Van Lint C Emiliani S Verdin E. (1996). The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr5: 245-253.
Voigt A Hartmann P and Zintl F. (2000). Differentiation proliferation and adhesion of human neuroblastoma cells after treatment with retinoic acid. Cell Adhes Commun7: 423-440.
Wen X Wang JS Kivistö KT Neuvonen PJ Backman JT. (2001). In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9). Br J Clin Pharmacol52: 547-553.