Skip to main content

Advertisement

SpringerLink
Log in

The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Glioblastoma multiforme (GBM) has nearly uniformly fatal with a median survival of less than 2 years. While there have not been any novel anti-GBM therapeutics approved for many years, there has been the gradual accumulation of clinical data suggesting that the widely used anti-convulsant agent, valproic acid (VPA) may significantly prolong survival in GBM patients. This pre-clinical study aimed to determine the potential clinical utility of VPA in the treatment of GBM. Primary GBM cells were treated with VPA as a monotherapy and in combination with temozolomide and irradiation. At clinically achievable concentrations, VPA was shown to be effective as a monotherapy agent in the five primary lines tested. VPA was then used as a sensitizing agent to in vitro radiation and showed significant augmentation of in vitro irradiation therapy. In addition, when VPA, radiation and temozolomide were combined an additive, rather than synergistic effect was noted. Gene expression profiling demonstrated close clustering of triple treated cells with VPA mono-treated cells while untreated cells clustered closer with TMZ-irradiation dual treated cells. These microarray data suggest a dominant role of VPA at the gene expression level when combining these different treatment options. Moreover, in an in vivo tumor transplantation model, we were able to demonstrate an increase in animal survival when cells were pre-treated with irradiation-VPA and when triple treated. These findings provide a significant rationale for the investigation of VPA in the treatment of GBM patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Johnson DR, O’Neill BP (2012) Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol 107(2):359–364

    Article  CAS  PubMed  Google Scholar 

  2. Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S et al (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24):6969–6978

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Jung M, Velena A, Chen B, Petukhov PA, Kozikowski AP, Dritschilo A (2005) Novel HDAC inhibitors with radiosensitizing properties. Radiat Res 163(5):488–493

    Article  CAS  PubMed  Google Scholar 

  4. Galanis E, Jaeckle KA, Maurer MJ, Reid JM, Ames MM, Hardwick JS et al (2009) Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study. J Clin Oncol 27(12):2052–2058

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Felix FH, Trompieri NM, de Araujo OL, da Trindade KM, Fontenele JB (2011) Potential role for valproate in the treatment of high-risk brain tumors of childhood-results from a retrospective observational cohort study. Pediatr Hematol Oncol 28(7):556–570

    Article  CAS  PubMed  Google Scholar 

  6. Weller M (2013) Are we ready for a randomized trial of valproic acid in newly diagnosed glioblastoma? Neuro-oncology 15(7):809–810

    Article  PubMed Central  PubMed  Google Scholar 

  7. Kerkhof M, Dielemans JC, van Breemen MS, Zwinkels H, Walchenbach R, Taphoorn MJ et al (2013) Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. Neuro-oncology 15(7):961–967

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA et al (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259

    Article  CAS  PubMed  Google Scholar 

  9. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729

    Article  CAS  PubMed  Google Scholar 

  10. Gilbert MR, Sulman EP, Mehta MP (2014) Bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(21):2048–2049

    Article  PubMed  Google Scholar 

  11. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R et al (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722

    Article  CAS  PubMed  Google Scholar 

  12. Cohen MH, Johnson JR, Pazdur R (2005) Food and Drug Administration Drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme. Clin Cancer Res 11(19 Pt 1):6767–6771

    Article  CAS  PubMed  Google Scholar 

  13. Stevens MF, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R et al (1987) Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47(22):5846–5852

    CAS  PubMed  Google Scholar 

  14. Brennand J, Margison GP (1986) Reduction of the toxicity and mutagenicity of alkylating agents in mammalian cells harboring the Escherichia coli alkyltransferase gene. Proc Natl Acad Sci USA 83(17):6292–6296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003

    Article  CAS  PubMed  Google Scholar 

  16. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  CAS  PubMed  Google Scholar 

  17. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466

    Article  CAS  PubMed  Google Scholar 

  18. Frosina G (2009) DNA repair and resistance of gliomas to chemotherapy and radiotherapy. Mol Cancer Res 7(7):989–999

    Article  CAS  PubMed  Google Scholar 

  19. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276(39):36734–36741

    Article  CAS  PubMed  Google Scholar 

  20. Chen Y, Tsai YH, Tseng SH (2012) Valproic acid affected the survival and invasiveness of human glioma cells through diverse mechanisms. J Neurooncol 109(1):23–33

    Article  CAS  PubMed  Google Scholar 

  21. Zhou Y, Xu Y, Wang H, Niu J, Hou H, Jiang Y (2014) Histone deacetylase inhibitor, valproic acid, radiosensitizes the C6 glioma cell line. Oncol Lett 7(1):203–208

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Chen J, Ghazawi FM, Bakkar W, Li Q (2006) Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B. Mol Cancer 5:71

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Van Nifterik KA, Van den Berg J, Slotman BJ, Lafleur MV, Sminia P, Stalpers LJ (2012) Valproic acid sensitizes human glioma cells for temozolomide and gamma-radiation. J Neurooncol 107(1):61–67

    Article  CAS  PubMed  Google Scholar 

  24. Peterson GM, Naunton M (2005) Valproate: a simple chemical with so much to offer. J Clin Pharm Ther 30(5):417–421

    Article  CAS  PubMed  Google Scholar 

  25. Day BW, Stringer BW, Al-Ejeh F, Ting MJ, Wilson J, Ensbey KS et al (2013) EphA3 maintains tumorigenicity and is a therapeutic target in glioblastoma multiforme. Cancer Cell 23(2):238–248

    Article  CAS  PubMed  Google Scholar 

  26. Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98(9):5116–5121

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Engelhard HH, Duncan HA, Kim S, Criswell PS, Van Eldik L (2001) Therapeutic effects of sodium butyrate on glioma cells in vitro and in the rat C6 glioma model. Neurosurgery 48(3):616–624 discussion 24–5

    Article  CAS  PubMed  Google Scholar 

  28. Ji Q, Shi X, Lin R, Mao Y, Zhai X, Lin Q et al (2010) Participation of lipid transport and fatty acid metabolism in valproate sodium-induced hepatotoxicity in HepG2 cells. Toxicol In Vitro 24(4):1086–1091

    Article  CAS  PubMed  Google Scholar 

  29. Hu W, Sorrentino C, Denison MS, Kolaja K, Fielden MR (2007) Induction of cyp1a1 is a nonspecific biomarker of aryl hydrocarbon receptor activation: results of large scale screening of pharmaceuticals and toxicants in vivo and in vitro. Mol Pharmacol 71(6):1475–1486

    Article  CAS  PubMed  Google Scholar 

  30. Dokmanovic M, Marks PA (2005) Prospects: histone deacetylase inhibitors. J Cell Biochem 96(2):293–304

    Article  CAS  PubMed  Google Scholar 

  31. Xu WS, Parmigiani RB, Marks PA (2007) Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene 26(37):5541–5552

    Article  CAS  PubMed  Google Scholar 

  32. Friedmann I, Atmaca A, Chow KU, Jager E, Weidmann E (2006) Synergistic effects of valproic acid and mitomycin C in adenocarcinoma cell lines and fresh tumor cells of patients with colon cancer. J Chemother 18(4):415–420

    Article  CAS  PubMed  Google Scholar 

  33. Thelen P, Schweyer S, Hemmerlein B, Wuttke W, Seseke F, Ringert RH (2004) Expressional changes after histone deacetylase inhibition by valproic acid in LNCaP human prostate cancer cells. Int J Oncol 24(1):25–31

    CAS  PubMed  Google Scholar 

  34. Olsen CM, Meussen-Elholm ET, Roste LS, Tauboll E (2004) Antiepileptic drugs inhibit cell growth in the human breast cancer cell line MCF7. Mol Cell Endocrinol 213(2):173–179

    Article  CAS  PubMed  Google Scholar 

  35. Debeb BG, Xu W, Mok H, Li L, Robertson F, Ueno NT et al (2010) Differential radiosensitizing effect of valproic acid in differentiation versus self-renewal promoting culture conditions. Int J Radiat Oncol Biol Phys 76(3):889–895

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Li XN, Shu Q, Su JM, Perlaky L, Blaney SM, Lau CC (2005) Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol Cancer Ther 4(12):1912–1922

    Article  CAS  PubMed  Google Scholar 

  37. Li XN, Parikh S, Shu Q, Jung HL, Chow CW, Perlaky L et al (2004) Phenylbutyrate and phenylacetate induce differentiation and inhibit proliferation of human medulloblastoma cells. Clin Cancer Res 10(3):1150–1159

    Article  CAS  PubMed  Google Scholar 

  38. Chen X, Wong JY, Wong P, Radany EH (2011) Low-dose valproic acid enhances radiosensitivity of prostate cancer through acetylated p53-dependent modulation of mitochondrial membrane potential and apoptosis. Mol Cancer Res 9(4):448–461

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Nyskohus LS, Watson AJ, Margison GP, Le Leu RK, Kim SW, Lockett TJ et al (2013) Repair and removal of azoxymethane-induced O6-methylguanine in rat colon by O6-methylguanine DNA methyltransferase and apoptosis. Mutat Res 758(1–2):80–86

    Article  CAS  PubMed  Google Scholar 

  40. Weller M, Gorlia T, Cairncross JG, van den Bent MJ, Mason W, Belanger K et al (2011) Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 77(12):1156–1164

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Barker CA, Bishop AJ, Chang M, Beal K, Chan TA (2013) Valproic acid use during radiation therapy for glioblastoma associated with improved survival. Int J Radiat Oncol Biol Phys 86(3):504–509

    Article  CAS  PubMed  Google Scholar 

  42. Masoudi A, Elopre M, Amini E, Nagel ME, Ater JL, Gopalakrishnan V et al (2008) Influence of valproic acid on outcome of high-grade gliomas in children. Anticancer Res 28(4C):2437–2442

    PubMed  Google Scholar 

  43. Felix FH, de Araujo OL, da Trindade KM, Trompieri NM, Fontenele JB (2014) Retrospective evaluation of the outcomes of children with diffuse intrinsic pontine glioma treated with radiochemotherapy and valproic acid in a single center. J Neurooncol 116(2):261–266

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

RBWH Department of Neurosurgery, RBWH patients with GBM consenting for brain cancer research on resected tissue, Rotary Rockhampton, RBWH Division of Cancer Care and RBWH Foundation for funding the brain biobank at QIMR. Experiments were approved by the human ethics committee of the Queensland Institute of Medical Research (QIMR) and Royal Brisbane and Women’s Hospital (RBWH).

Conflict of interest

Authors have no conficts of interest to declare.

Funding

Royal Brisbane and Women’s Hospital Foundation, Rotary Rockhampton, Cancer Council Queensland.

Author information

Authors and Affiliations

  1. Diamantina Institute and School of Medicine, University of Queensland, Brisbane, Australia

    Abdel Nasser Hosein & Jennifer H. Martin

  2. Queensland Institute of Medical Research/Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia

    Abdel Nasser Hosein, Yi Chieh Lim, Bryan Day & Brett Stringer

  3. The Australian e-Health Research Centre, Digital Productivity & Services Flagship; CSIRO, Royal Brisbane and Women’s Hospital, Level 5 UQ Health Science Building 901/16, Herston, 4029, Australia

    Stephen Rose

  4. Chancellery, University of South Australia, Level 4, Hawke Building, GPO Box 2471, Adelaide, SA, 5001, Australia

    Richard Head

  5. CSIRO, Adelaide, PO Box 10041, Adelaide BC, SA, 5000, Australia

    Leah Cosgrove

  6. Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands

    Peter Sminia

  7. Department of Radiation Oncology, Royal Brisbane and Women’s Hospital, Butterfield St, Herston, QLD, 4006, Australia

    Michael Fay

  8. Department of Clinical Pharmacology, University of Newcastle School of Medicine and Public Health, Callaghan, NSW, Australia

    Jennifer H. Martin

Authors
  1. Abdel Nasser Hosein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi Chieh Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bryan Day
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brett Stringer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard Head
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leah Cosgrove
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Sminia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael Fay
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jennifer H. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer H. Martin.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 64 kb)

Supplementary material 2 (DOCX 11 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hosein, A.N., Lim, Y.C., Day, B. et al. The effect of valproic acid in combination with irradiation and temozolomide on primary human glioblastoma cells. J Neurooncol 122, 263–271 (2015). https://doi.org/10.1007/s11060-014-1713-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1713-x

Keywords

Search

Navigation