Skip to main content

Advertisement

SpringerLink
Log in

Viability of D283 medulloblastoma cells treated with a histone deacetylase inhibitor combined with bombesin receptor antagonists

  • Brief Communication
  • Published:
Child's Nervous System Aims and scope Submit manuscript

Abstract

Purpose

Medulloblastoma (MB) comprises four distinct molecular subgroups, and survival remains particularly poor in patients with Group 3 tumors. Mutations and copy number variations result in altered epigenetic regulation of gene expression in Group 3 MB. Histone deacetylase inhibitors (HDACi) reduce proliferation, promote cell death and neuronal differentiation, and increase sensitivity to radiation and chemotherapy in experimental MB. Bombesin receptor antagonists potentiate the antiproliferative effects of HDACi in lung cancer cells and show promise as experimental therapies for several human cancers. Here, we examined the viability of D283 cells, which belong to Group 3 MB, treated with an HDACi alone or combined with bombesin receptor antagonists.

Methods

D283 MB cells were treated with different doses of the HDACi sodium butyrate (NaB), the neuromedin B receptor (NMBR) antagonist BIM-23127, the gastrin releasing peptide receptor (GRPR) antagonist RC-3095, or combinations of NaB with each receptor antagonist. Cell viability was examined by cell counting.

Results

NaB alone or combined with receptor antagonists reduced cell viability at all doses tested. BIM-23127 alone did not affect cell viability, whereas RC-3095 at an intermediate dose significantly increased cell number.

Conclusion

Although HDACi are promising agents to inhibit MB growth, the present results provide preliminary evidence that combining HDACi with bombesin receptor antagonists is not an effective strategy to improve the effects of HDACi against MB cells.

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

References

  1. Polkinghorn WR, Tarbell NJ (2007) Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol 4:295–304

    Article  CAS  PubMed  Google Scholar 

  2. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V, Goumnerova L, Eberhart CG, Lau CC, Olson JM, Gilbertson RJ, Gajjar A, Delattre O, Kool M, Ligon K, Meyerson M, Mesirov JP, Pomeroy SL (2011) Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29:1424–1430

    Article  PubMed Central  PubMed  Google Scholar 

  4. Friedman HS, Burger PC, Bigner SH, Trojanowski JQ, Wikstrand CJ, Halperin EC, Bigner DD (1985) Establishment and characterization of the human medulloblastoma cell line and transplantable xenograft D283 Med. J Neuropathol Exp Neurol 44:592–605

    Article  CAS  PubMed  Google Scholar 

  5. Xu J, Margol A, Asgharzadeh S, Erdreich-Epstein A (2015) Pediatric brain tumor cell lines. J Cell Biochem 116:218–224

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Northcott PA, Nakahara Y, Wu X, Feuk L, Ellison DW, Croul S, Mack S, Kongkham PN, Peacock J, Dubuc A, Ra YS, Zilberberg K, McLeod J, Scherer SW, Sunil Rao J, Eberhart CG, Grajkowska W, Gillespie Y, Lach B, Grundy R, Pollack IF, Hamilton RL, Van Meter T, Carlotti CG, Boop F, Bigner D, Gilbertson RJ, Rutka JT, Taylor MD (2009) Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet 41:465–472

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Dubuc AM, Remke M, Korshunov A, Northcott PA, Zhan SH, Mendez-Lago M, Kool M, Jones DT, Unterberger A, Morrissy AS, Shih D, Peacock J, Ramaswamy V, Rolider A, Wang X, Witt H, Hielscher T, Hawkins C, Vibhakar R, Croul S, Rutka JT, Weiss WA, Jones SJ, Eberhart CG, Marra MA, Pfister SM, Taylor MD (2013) Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol 125:373–384

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Ecker J, Oehme I, Mazitschek R, Korshunov A, Kool M, Hielscher T, Kiss J, Selt F, Konrad C, Lodrini M, Deubzer HE, von Deimling A, Kulozik AE, Pfister SM, Witt O, Milde T (2015) Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma. Acta Neuropathol Commun 3:22

    Article  PubMed Central  PubMed  Google Scholar 

  10. Sonnemann J, Kumar KS, Heesch S, Müller C, Hartwig C, Maass M, Bader P, Beck JF (2006) Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells. Int J Oncol 28:755–766

    CAS  PubMed  Google Scholar 

  11. Nör C, Sassi FA, de Farias CB, Schwartsmann G, Abujamra AL, Lenz G, Brunetto AL, Roesler R (2013) The histone deacetylase inhibitor sodium butyrate promotes cell death and differentiation and reduces neurosphere formation in human medulloblastoma cells. Mol Neurobiol 48:533–543

    Article  PubMed  Google Scholar 

  12. 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 4:1912–1922

    Article  CAS  PubMed  Google Scholar 

  13. Schmidt AL, Brunetto AL, Schwartsmann G, Roesler R, Abujamra AL (2010) Recent therapeutic advances for treating medulloblastoma: focus on new molecular targets. CNS Neurol Disord Drug Targets 9:335–348

    Article  CAS  PubMed  Google Scholar 

  14. Jensen RT, Battey JF, Spindel ER, Benya RV (2008) International union of pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacol Rev 60:1–42

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Cornelio DB, Roesler R, Schwartsmann G (2007) Gastrin-releasing peptide receptor as a molecular target in experimental anticancer therapy. Ann Oncol 18:1457–1466

    Article  CAS  PubMed  Google Scholar 

  16. Moody TW, Nakagawa T, Kang Y, Jakowlew S, Chan D, Jensen RT (2006) Bombesin/gastrin-releasing peptide receptor antagonists increase the ability of histone deacetylase inhibitors to reduce lung cancer proliferation. J Mol Neurosci 28:231–238

    Article  CAS  PubMed  Google Scholar 

  17. Abujamra AL, Almeida VR, Brunetto AL, Schwartsmann G, Roesler R (2009) A gastrin-releasing peptide receptor antagonist stimulates Neuro2a neuroblastoma cell growth: prevention by a histone deacetylase inhibitor. Cell Biol Int 33:899–903

    Article  CAS  PubMed  Google Scholar 

  18. Jaeger M, Nör C, de Farias CB, Abujamra AL, Schwartsmann G, Brunetto AL, Roesler R (2013) Anti-EGFR therapy combined with neuromedin B receptor blockade induces the death of DAOY medulloblastoma cells. Childs Nerv Syst 29:2145–2150

    Article  PubMed  Google Scholar 

  19. Schmidt AL, de Farias CB, Abujamra AL, Kapczinski F, Schwartsmann G, Brunetto AL, Roesler R (2010) BDNF and PDE4, but not the GRPR, regulate viability of human medulloblastoma cells. J Mol Neurosci 40:303–310

    Article  CAS  PubMed  Google Scholar 

  20. Pinski J, Schally AV, Halmos G, Szepeshazi K, Groot K (1994) Somatostatin analogues and bombesin/gastrin-releasing peptide antagonist RC-3095 inhibit the growth of human glioblastomas in vitro and in vivo. Cancer Res 54:5895–5901

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was supported by the National Council for Scientific and Technological Development (CNPq; grant numbers 484185/2012-8 and 303276/2013-4 to R.R.); PRONON/Ministry of Health, Brazil (number 25000.162.034/2014-21 to C.B.F); the Rafael Koff Acordi Research Fund, Children’s Cancer Institute (ICI); the South American Office for Anticancer Drug Development; and the Clinical Hospital institutional research fund (FIPE/HCPA).

Author information

Authors and Affiliations

  1. Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Mariane Jaeger, Eduarda C. Ghisleni, Lívia Fratini, Algemir L. Brunetto, Gilberto Schwartsmann, Caroline B. de Farias & Rafael Roesler

  2. Children’s Cancer Institute (ICI), Porto Alegre, RS, Brazil

    Algemir L. Brunetto, André T. Brunetto & Caroline B. de Farias

  3. Department of Pediatrics, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Lauro José Gregianin

  4. Department of Internal Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Gilberto Schwartsmann

  5. Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), Porto Alegre, RS, 90050-170, Brazil

    Rafael Roesler

Authors
  1. Mariane Jaeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eduarda C. Ghisleni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lívia Fratini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Algemir L. Brunetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lauro José Gregianin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. André T. Brunetto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gilberto Schwartsmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Caroline B. de Farias
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rafael Roesler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rafael Roesler.

Ethics declarations

All experimental procedures were approved by the institutional research ethics committee (GPPG-HCPA). The present study does not involve the use of experimental animals or materials obtained from patients.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jaeger, M., Ghisleni, E.C., Fratini, L. et al. Viability of D283 medulloblastoma cells treated with a histone deacetylase inhibitor combined with bombesin receptor antagonists. Childs Nerv Syst 32, 61–64 (2016). https://doi.org/10.1007/s00381-015-2963-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00381-015-2963-4

Keywords

Search

Navigation