Antitumor effects of a combined 5-aza-2′deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice

Ines Ecke, Frauke Petry, Albert Rosenberger, Svantje Tauber, Sven Mönkemeyer, Ina Hess, Christian Dullin, Sarah Kimmina, Judith Pirngruber, Steven A. Johnsen, Anja Uhmann, Frauke Nitzki, Leszek Wojnowski, Walter Schulz-Schaeffer, Olaf Witt, Heidi Hahn

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Patched (Ptch) heterozygous mice develop medulloblastoma (MB) and rhabdomyosarcoma (RMS) resembling the corresponding human tumors. We have previously shown that epigenetic silencing of the intact Ptch allele contributes to tumor formation in this model. Here,we investigated whether targeting of epigenetic silencing mechanisms could be useful in the treatment of Ptch-associated cancers. A reduction of endogenous DNA methyltransferase1 (Dnmt1) activity significantly reduced tumor incidence in heterozygous Ptch knockout mice. A combined treatment with the Dnmt inhibitor 5-aza- 2′deoxycytidine (5-aza-dC) and the histone deacetlyase (HDAC) inhibitor valproic acid (VPA) efficiently prevented MB and RMS formation, whereas monotherapies with either drug were less effective. Wild-type Ptch expression was efficiently reactivated in tumors by 5-aza-dC/VPA combination therapy. This was associated with reduced methylation of the Ptch promoter and induction of histone hyperacetylation suggesting inhibition of HDACs in vivo. However, the treatment was not effective in clinically overt, advanced stage tumors. This is a first in vivo demonstration that targeting of Dnmt and HDAC activities is highly effective in preventing formation of Ptch-associated tumors. The results suggest a novel clinical strategy for consolidation therapy of corresponding tumors in humans after completion of conventional treatment. Our data also suggest that epigenetic therapy may be less effective in treating advanced stages of tumors, at least in this tumor model.

Original languageEnglish (US)
Pages (from-to)887-895
Number of pages9
JournalCancer research
Volume69
Issue number3
DOIs
StatePublished - Feb 1 2009

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ecke, I., Petry, F., Rosenberger, A., Tauber, S., Mönkemeyer, S., Hess, I., Dullin, C., Kimmina, S., Pirngruber, J., Johnsen, S. A., Uhmann, A., Nitzki, F., Wojnowski, L., Schulz-Schaeffer, W., Witt, O., & Hahn, H. (2009). Antitumor effects of a combined 5-aza-2′deoxycytidine and valproic acid treatment on rhabdomyosarcoma and medulloblastoma in Ptch mutant mice. Cancer research, 69(3), 887-895. https://doi.org/10.1158/0008-5472.CAN-08-0946