title: The ATRA-induced differentiation of medulloblastoma cells is enhanced with LOX/COX inhibitors: an analysis of gene expression.
abstract: BACKGROUND
  A detailed analysis of the expression of 440 cancer-related genes was performed after the combined treatment of medulloblastoma cells with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). The combinations of retinoids and celecoxib as a COX-2 inhibitor were reported to be effective in some regimens of metronomic therapy of relapsed solid tumors with poor prognosis. Our previous findings on neuroblastoma cells using expression profiling showed that LOX/COX inhibitors have the capability of enhancing the differentiating action of ATRA. Presented study focused on the continuation of our previous work to confirm the possibility of enhancing ATRA-induced cell differentiation in these cell lines via the application of LOX/COX inhibitors. This study provides more detailed information concerning the mechanisms of the enhancement of the ATRA-induced differentiation of medulloblastoma cells.
  
  
  METHODS
  The Daoy and D283 Med medulloblastoma cell lines were chosen for this study. Caffeic acid (an inhibitor of 5-LOX) and celecoxib (an inhibitor on COX-2) were used in combined treatment with ATRA. The expression profiling was performed using Human Cancer Oligo GEArray membranes, and the most promising results were verified using RT-PCR.
  
  
  RESULTS
  The expression profiling of the selected cancer-related genes clearly confirmed that the differentiating effects of ATRA should be enhanced via its combined administration with caffeic acid or celecoxib. This effect was detected in both cell lines. An increased expression of the genes that encoded the proteins participating in induced differentiation and cytoskeleton remodeling was detected in both cell lines in a concentration-dependent manner. This effect was also observed for the CDKN1A gene encoding the p21 protein, which is an important regulator of the cell cycle, and for the genes encoding proteins that are associated with proteasome activity. Furthermore, our results showed that D283 Med cells are significantly more sensitive to treatment with ATRA alone than Daoy cells.
  
  
  CONCLUSIONS
  The obtained results on medulloblastoma cell lines are in accordance with our previous findings on neuroblastoma cells and confirm our hypothesis concerning the common mechanism of the enhancement of ATRA-induced cell differentiation in various types of pediatric solid tumors.
authors: Department of Experimental Biology - Laboratory of Tumor Biology, School of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic.
authors: Petr
authors: P
authors: Chlapek
authors: Department of Experimental Biology - Laboratory of Tumor Biology, School of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic ; Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
authors: Jakub
authors: J
authors: Neradil
authors: Department of Experimental Biology - Laboratory of Tumor Biology, School of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic.
authors: Martina
authors: M
authors: Redova
authors: Department of Experimental Biology - Laboratory of Tumor Biology, School of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic ; Department of Pediatric Oncology, University Hospital Brno and School of Medicine, Masaryk University, Cernopolni 9, 613 00 Brno, Czech Republic.
authors: Karel
authors: K
authors: Zitterbart
authors: Department of Pediatric Oncology, University Hospital Brno and School of Medicine, Masaryk University, Cernopolni 9, 613 00 Brno, Czech Republic ; Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
authors: Jaroslav
authors: J
authors: Sterba
authors: Department of Experimental Biology - Laboratory of Tumor Biology, School of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic ; Department of Pediatric Oncology, University Hospital Brno and School of Medicine, Masaryk University, Cernopolni 9, 613 00 Brno, Czech Republic.
authors: Renata
authors: R
authors: Veselska
keywords: All-trans retinoic acid; Caffeic acid; Celecoxib; LOX and COX inhibitors; Medullobastoma