The main objective of this study was to analyze changes in the antiproliferative effect of vitamin D3, in the form of calcitriol and calcidiol, via its combined application with all-trans retinoic acid (ATRA) in osteosarcoma cell lines. The response to treatment with calcitriol and calcidiol alone was specific for each cell line. Nevertheless, we observed an enhanced effect of combined treatment with ATRA and calcitriol in the majority of the cell lines. Although the levels of respective nuclear receptors did not correlate with the sensitivity of cells to these drugs, vitamin D receptor (VDR) upregulation induced by ATRA was found in cell lines that were the most sensitive to the combined treatment. In addition, all these cell lines showed high endogenous levels of retinoic acid receptor α (RARα). Our study confirmed that the combination of calcitriol and ATRA can achieve enhanced antiproliferative effects in human osteosarcoma cell lines in vitro. Moreover, we provide the first evidence that ATRA is able to upregulate VDR expression in human osteosarcoma cells. According to our results, the endogenous levels of RARα and VDR could be used as a predictor of possible synergy between ATRA and calcitriol in osteosarcoma cells.

Department of Pediatric Oncology University Hospital Brno and Faculty of Medicine Masaryk University Cernopolni 9 61300 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Pekarska 53 65691 Brno Czech Republic

Laboratory of Tumor Biology Department of Experimental Biology Faculty of Science Masaryk University Kotlarska 2 61137 Brno Czech Republic

Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Zluty kopec 7 65653 Brno Czech Republic

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