Oncotarget

Research Papers:

Inhibition of 13-cis retinoic acid-induced gene expression of reactive-resistance genes by thalidomide in glioblastoma tumours in vivo

Dusan Milanovic _, Carsten Sticht, Manuel Röhrich, Patrick Maier, Anca-L Grosu and Carsten Herskind

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Oncotarget. 2015; 6:28938-28948. https://doi.org/10.18632/oncotarget.4727

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Abstract

Dusan Milanovic1,2,3, Carsten Sticht4, Manuel Röhrich5, Patrick Maier6, Anca-L. Grosu1,2,3, Carsten Herskind6

1Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany

2German Cancer Consortium (DKTK), Freiburg, Germany

3German Cancer Research Center (DKFZ), Heidelberg, Germany

4Centre for Medical Research, Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

5Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany

6Department of Radiation Oncology, Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

Correspondence to:

Dusan Milanovic, e-mail: dusan.milanovic@uniklinik-freiburg.de

Keywords: glioblastoma, 13-cis retinoic acid, thalidomide, hypoxia, angiogenesis

Received: January 29, 2015     Accepted: July 20, 2015     Published: July 30, 2015

ABSTRACT

The cell differentiation potential of 13-cis retinoic acid (RA) has not succeeded in the clinical treatment of glioblastoma (GBM) so far. However, RA may also induce the expression of resistance genes such as HOXB7 which can be suppressed by Thalidomide (THAL). Therefore, we tested if combined treatment with RA+THAL may inhibit growth of glioblastoma in vivo. Treatment with RA+THAL but not RA or THAL alone significantly inhibited tumour growth. The synergistic effect of RA and THAL was corroborated by the effect on proliferation of glioblastoma cell lines in vitro. HOXB7 was not upregulated but microarray analysis validated by real-time PCR identified four potential resistance genes (IL-8, HILDPA, IGFBPA, and ANGPTL4) whose upregulation by RA was suppressed by THAL. Furthermore, genes coding for small nucleolar RNAs (snoRNA) were identified as a target for RA for the first time, and their upregulation was maintained after combined treatment. Pathway analysis showed upregulation of the Ribosome pathway and downregulation of pathways associated with proliferation and inflammation. In conclusion, combined treatment with RA + THAL delayed growth of GBM xenografts and suppressed putative resistance genes associated with hypoxia and angiogenesis. This encourages further pre-clinical and clinical studies of this drug combination in GBM.


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