The induced differentiation of tumor cells into mature phenotypes is a promising strategy in cancer therapy. In this study, the effects of combined treatment with all-trans retinoic acid (ATRA) and lipoxygenase/cyclooxygenase inhibitors were examined in two osteosarcoma cell lines, Saos-2 and OSA-01. Caffeic acid and celecoxib were used as inhibitors of 5-lipoxygenase and of cyclooxygenase-2, respectively. Changes in the cell proliferation, matrix mineralization, and occurrence of differentiation markers were evaluated in treated cell populations at intervals. The results confirmed the capability of caffeic acid to enhance the antiproliferative effect of ATRA in both cell lines. In contrast, celecoxib showed the same effect in Saos-2 cells only. Furthermore, the extension of matrix mineralization was observed after combined treatment with ATRA and celecoxib or caffeic acid. The increased expression of osteogenic differentiation markers was observed in both cell lines after the combined application of ATRA and inhibitors. The obtained results clearly demonstrate the capability of lipoxygenase/cyclooxygenase inhibitors to enhance the antiproliferative and differentiating effect of ATRA in osteosarcoma cells, although some of these effects are specific and depend on the biological features of the respective tumor or cell line.

• MeSH
• Antineoplastic Agents pharmacology   MeSH
• Cell Differentiation drug effects   MeSH
• Celecoxib MeSH
• Cyclooxygenase Inhibitors pharmacology   MeSH
• Lipoxygenase Inhibitors pharmacology   MeSH
• Caffeic Acids pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Bone Neoplasms drug therapy   pathology   MeSH
• Osteosarcoma drug therapy   pathology   MeSH
• Cell Proliferation drug effects   MeSH
• Pyrazoles pharmacology   MeSH
• Sulfonamides pharmacology   MeSH
• Tretinoin pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antineoplastic Agents MeSH
• caffeic acid MeSH Browser
• Celecoxib MeSH
• Cyclooxygenase Inhibitors MeSH
• Lipoxygenase Inhibitors MeSH
• Caffeic Acids MeSH
• Pyrazoles MeSH
• Sulfonamides MeSH
• Tretinoin MeSH

BACKGROUND: We performed expression profiling of two neuroblastoma cell lines, SK-N-BE(2) and SH-SY5Y, after combined treatment with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). This study is a continuation of our previous work confirming the possibility of enhancing ATRA-induced cell differentiation in these cell lines by the application of LOX/COX inhibitors and brings more detailed information concerning the mechanisms of the enhancement of ATRA-induced differentiation of neuroblastoma cells. METHODS: Caffeic acid, as an inhibitor of 5-lipoxygenase, and celecoxib, as an inhibitor on cyclooxygenase-2, were used in this study. Expression profiling was performed using Human Cancer Oligo GEArray membranes that cover 440 cancer-related genes. RESULTS: Cluster analyses of the changes in gene expression showed the concentration-dependent increase in genes known to be involved in the process of retinoid-induced neuronal differentiation, especially in cytoskeleton remodeling. These changes were detected in both cell lines, and they were independent of the type of specific inhibitors, suggesting a common mechanism of ATRA-induced differentiation enhancement. Furthermore, we also found overexpression of some genes in the same cell line (SK-N-BE(2) or SH-SY5Y) after combined treatment with both ATRA and CA, or ATRA and CX. Finally, we also detected that gene expression was changed after treatment with the same inhibitor (CA or CX) in combination with ATRA in both cell lines. CONCLUSIONS: Obtained results confirmed our initial hypothesis of the common mechanism of enhancement in ATRA-induced cell differentiation via inhibition of arachidonic acid metabolic pathway.

• MeSH
• Cell Differentiation drug effects   MeSH
• Celecoxib MeSH
• Cyclooxygenase Inhibitors pharmacology   MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Lipoxygenase Inhibitors pharmacology   MeSH
• Caffeic Acids pharmacology   MeSH
• Humans MeSH
• Multigene Family MeSH
• Brain Neoplasms drug therapy   pathology   MeSH
• Neuroblastoma drug therapy   pathology   MeSH
• Oxidative Stress MeSH
• Pyrazoles pharmacology   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Gene Expression Profiling MeSH
• Sulfonamides pharmacology   MeSH
• Tretinoin metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• caffeic acid MeSH Browser
• Celecoxib MeSH
• Cyclooxygenase Inhibitors MeSH
• Enzyme Inhibitors MeSH
• Lipoxygenase Inhibitors MeSH
• Caffeic Acids MeSH
• Pyrazoles MeSH
• Sulfonamides MeSH
• Tretinoin MeSH