Skip to main content

Advertisement

SpringerLink
Log in

Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA)

  • Lab investigation - human/animal tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Purpose Current medulloblastoma therapy, surgery, radiation, and chemotherapy, is unacceptably toxic. However, 13-cis retinoic acid (RA) and SAHA, a histone deacetylase inhibitor, have each been shown to induce apoptosis in medulloblastoma cultures and mouse models. Both drugs cross the blood brain barrier, have been given safely to children, and achieve brain concentrations that are at or near therapeutic levels. Retinoic acid acts by transcriptionally activating bone morphogenetic protein-2 (BMP-2) and SAHA facilitates transcriptional activity through chromatin accessibility. We tested the hypothesis that these drugs additively induce BMP-2 transcription and apoptosis. Experimental design RA + SAHA induction of BMP-2 transcription and apoptosis in medulloblastoma cultures was evaluated. Subsequently the response of mouse medulloblastomas to these two agents in the presence and absence of cisplatin was evaluated. Results BMP-2 transcription multiplied 3-fold with addition of RA to culture, and 7-fold with both agents. The IC50 of SAHA was reduced by 40% when low dose RA was added. Interestingly, a p38 MAP kinase inhibitor that partially blocks RA-induced apoptosis did not inhibit the activity of RA + SAHA. Flank D283 tumors in athymic mice had slower growth in the RA + SAHA arm than single drug or control arms. Intracranial tumors in ND2:SmoA1 mice treated with RA + SAHA + cisplatin showed a 4-fold increase in apoptosis over controls, and a 2-fold increase over animals receiving only SAHA or RA + SAHA. Conclusions RA + SAHA additively induce BMP-2 transcription and medulloblastoma apoptosis. The combination may act through a p38 MAPK independent mechanism. Efficacy increased with cisplatin, which has implications for clinical trial design.

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. McNeil DE, Cote TR, Clegg L, Rorke LB (2002) Incidence and trends in pediatric malignancies medulloblastoma/primitive neuroectodermal tumor: a SEER update. Med Pediatr Oncol 39:190–194

    Article  PubMed  Google Scholar 

  2. Gilbertson RJ (2004) Medulloblastoma: signalling a change in treatment. Lancet Oncol 5:209–218

    Article  PubMed  Google Scholar 

  3. Geyer JR, Sposto R, Jennings M et al (2005) Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group. J Clin Oncol 23:7621–7631

    Article  PubMed  Google Scholar 

  4. Silber JH, Radcliffe J, Peckham V et al (1992) Whole-brain irradiation and decline in intelligence: the influence of dose and age on IQ score. J Clin Oncol 10:1390–1396

    PubMed  CAS  Google Scholar 

  5. Hoppe-Hirsch E, Renier D, Lellouch-Tubiana A, Sainte-Rose C, Pierre-Kahn A, Hirsch JF (1990) Medulloblastoma in childhood: progressive intellectual deterioration. Childs Nerv Syst 6:60–65

    Article  PubMed  CAS  Google Scholar 

  6. Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM (2001) Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol 19:3470–3476

    PubMed  CAS  Google Scholar 

  7. Copeland DR, deMoor C, Moore BD, Ater JL (1999) Neurocognitive development of children after a cerebellar tumor in infancy: a longitudinal study. J Clin Oncol 17:3476–3486

    PubMed  CAS  Google Scholar 

  8. Xu W, Janss A, Packer RJ, Phillips P, Goldwein J, Moshang T (2004) Endocrine outcome in children with medulloblastoma treated with 18 Gy of craniospinal radiation therapy. Neuro-Oncology 6:113–118

    Article  PubMed  Google Scholar 

  9. Ranke MB, Price DA, Lindberg A, Wilton P, Darendeliler F, Reiter EO (2005) Final height in children with medulloblastoma treated with growth hormone. Horm Res 64:28–34

    Article  PubMed  CAS  Google Scholar 

  10. Knight KRG, Kraemer DF, Neuwelt EA (2005) Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 23:8588–8596

    Article  PubMed  Google Scholar 

  11. Miller WH (1998) The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer. Cancer 83:1471–1482

    Article  PubMed  CAS  Google Scholar 

  12. Hallahan AR, Pritchard JI, Chandraratna RA et al (2003) BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect. Nat Med 9:1033–1038

    Article  PubMed  CAS  Google Scholar 

  13. Spiller SE, Ravanpay AC, Hahn AW, Olson JM (2006) Suberoylanilide hydroxamic acid is effective in preclinical studies of medulloblastoma. J Neurooncol 79:259–270

    Article  PubMed  CAS  Google Scholar 

  14. Chinnaiyan P, Vallabhaneni G, Armstrong E, Huang SM, Harari PM (2005) Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 62:223–229

    Article  PubMed  CAS  Google Scholar 

  15. Sonnemann J, Kumar KS, Heesch S et al (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

    PubMed  CAS  Google Scholar 

  16. Hallahan AR, Pritchard JI, Hansen S et al (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64:7794–7800

    Article  PubMed  CAS  Google Scholar 

  17. Khan AA, Villablanca JG, Reynolds CP, Avramis VI (1996) Pharmacokinetic studies of 13-cis-retinoic acid in pediatric patients with neuroblastoma following bone marrow transplantation. Cancer Chemother Pharmacol 39:34–41

    Article  PubMed  CAS  Google Scholar 

  18. Freemantle SJ, Spinella MJ, Dmitrovsky E (2003) Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene 22:7305–7315

    Article  PubMed  CAS  Google Scholar 

  19. Henderson C, Mizzau M, Paroni G, Maestro R, Schneider C, Brancolini (2003) Role of caspases, Bid, and p53 in the apoptotic response triggered by histone deacetylase inhibitors trichostatin–A (TSA) and suberoylanilide hydroxamic acid (SAHA). J Biol Chem 278(14):12579–12589

    Article  PubMed  CAS  Google Scholar 

  20. Shao Y, Gao Z, Marks PA, Jiang X (2004) Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci U S A 101:18030–18035

    Article  PubMed  CAS  Google Scholar 

  21. Coffey DC, Kutko MC, Glick RD et al (2001) The histone deacetylase inhibitor, CBHA, inhibits growth of human neuroblastoma xenografts in vivo, alone and synergistically with all-trans retinoic acid. Cancer Res 61:3591–3594

    PubMed  CAS  Google Scholar 

  22. Wang X, Qian DZ, Ren M et al (2005) Epigenetic modulation of retinoic acid receptor β2 by the histone deacetylase inhibitor MS-275 in human renal cell carcinoma. Clin Cancer Res 11:3535–3542

    Article  PubMed  CAS  Google Scholar 

  23. Touma SE, Goldberg JS, Moench P et al (2005) Retinoic acid and the histone deacetylase inhibitor trichostatin A inhibit the proliferation of human renal cell carcinoma in a xenograft tumor model. Clin Cancer Res 11:3558–3566

    Article  PubMed  CAS  Google Scholar 

  24. Ferrara FF, Fazi F, Bianchini A et al (2001) Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 61:2–7

    PubMed  Google Scholar 

  25. Demary K, Wond L, Spanjaard RA (2001) Effects of retinoic acid and sodium butyrate on gene expression, histone acetylation and inhibition of proliferation of melanoma cells. Cancer Lett 163:103–108

    Article  PubMed  CAS  Google Scholar 

  26. NCI website: http://www.cancer.gov/clinicaltrials. Accessed May 15, 2007

  27. Packer RJ, Goldwin J, Nicholson HS et al (1999) Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children’s Cancer Group study. J Clin Oncol 17(7):2127–2136

    PubMed  CAS  Google Scholar 

  28. Aebi S, Kroning R, Cenni B et al (1999) All-trans retinoic acid enhances cisplatin-induced apoptosis in human ovarian adenocarcinoma and in squamous head and neck cancer cells. Clin Cancer Res 3:2033–2038

    Google Scholar 

  29. Kim MS, Blake M, Baek JH, Kohlhagen G, Pommier Y, Carrier F (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63:7291–7300

    PubMed  CAS  Google Scholar 

  30. Sato T, Suzuki M, Sato Y, Echigo S, Rikiishi H (2006) Sequence-dependent interaction between cisplatin and histone deacetylase inhibitors in human oral squamous cell carcinoma cells. Int J Oncol 28:1233–1241

    PubMed  CAS  Google Scholar 

  31. Pilatrino C, Cilloni D, Messa E et al (2005) Increase in platelet count in older, poor-risk patients with acute myeloid leukemia or myelodysplastic syndrome treated with valproic acid and all-trans retinoic acid. Cancer 104:101–109

    Article  PubMed  CAS  Google Scholar 

  32. Kuendgen A, Strupp C, Alvado M et al (2004) Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood 104:1266–1269

    Article  PubMed  CAS  Google Scholar 

  33. Bug G, Ritter M, Wassmann B et al (2005) Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer 104:2717–2725

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors wish to acknowledge Dr. Victoria Richon at Merck for her helpful discussions and generous contribution of SAHA. We also thank Dr. Andrew Hallahan and Stacey Hansen for helpful discussions, and Dr. Michael LeBlanc of the Southwest Oncology Group for assistance with statistical methods. This work was supported by NIH grants R01 CA114567-01A1 (JMO), R01 CA112350-02 (JMO), and U01 CA814547-07 (J. R. Geyer, PI) as well as the Damon Runyon Foundation (JMO) the Emily Dorfman Foundation through the American Brain Tumor Association (SES) and the Jordyn Dukelow Memorial Guild of Seattle Children’s Hospital (SES).

Author information

Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA, 98109, USA

    Susan E. Spiller, Sally H. Ditzler, Barbara J. Pullar & James M. Olson

  2. Department of Pediatrics, University of Washington and Children’s Hospital and Regional Medical Center, Seattle, WA, 98105, USA

    Susan E. Spiller & James M. Olson

Authors
  1. Susan E. Spiller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sally H. Ditzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara J. Pullar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. James M. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James M. Olson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spiller, S.E., Ditzler, S.H., Pullar, B.J. et al. Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA). J Neurooncol 87, 133–141 (2008). https://doi.org/10.1007/s11060-007-9505-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-007-9505-1

Keywords

Search

Navigation