Inhibition of 13-cis retinoic acid-induced gene expression of reactive-resistance genes by thalidomide in glioblastoma tumours in vivo
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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
Dusan Milanovic, e-mail: firstname.lastname@example.org
Keywords: glioblastoma, 13-cis retinoic acid, thalidomide, hypoxia, angiogenesis
Received: January 29, 2015 Accepted: July 20, 2015 Published: July 30, 2015
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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