tretinoin and caffeic-acid

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.

Topics: Antineoplastic Agents; Bone Neoplasms; Caffeic Acids; Celecoxib; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase Inhibitors; Humans; Lipoxygenase Inhibitors; Osteosarcoma; Pyrazoles; Sulfonamides; Tretinoin

We investigated the possible modulation by LOX/ COX inhibitors of all-trans retinoic acid (ATRA)-induced cell differentiation in two established neuroblastoma cell lines, SH-SY5Y and SK-N-BE(2). Caffeic acid, as an inhibitor of 5-lipoxygenase, and celecoxib, as an inhibitor of cyclooxygenase-2, were chosen for this study. The effects of the combined treatment with ATRA and LOX/COX inhibitors on neuroblastoma cells were studied using cell morphology assessment, detection of differentiation markers by immunoblotting, measurement of proliferation activity, and cell cycle analysis and apoptosis detection by flow cytometry. The results clearly demonstrated the potential of caffeic acid to enhance ATRA-induced cell differentiation, especially in the SK-N-BE(2) cell line, whereas application of celecoxib alone or with ATRA led predominantly to cytotoxic effects in both cell lines. Moreover, the higher sensitivity of the SK-N-BE(2) cell line to combined treatment with ATRA and LOX/COX inhibitors suggests that cancer stem cells are a main target for this therapeutic approach. Nevertheless, further detailed study of the phenomenon of enhanced cell differentiation by expression profiling is needed.

Topics: Apoptosis; Caffeic Acids; Celecoxib; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Shape; Cyclooxygenase 2 Inhibitors; Flow Cytometry; Humans; Lipoxygenase Inhibitors; Neuroblastoma; Pyrazoles; Sulfonamides; Tretinoin

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.. 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.. 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.. Obtained results confirmed our initial hypothesis of the common mechanism of enhancement in ATRA-induced cell differentiation via inhibition of arachidonic acid metabolic pathway.

Topics: Brain Neoplasms; Caffeic Acids; Celecoxib; Cell Differentiation; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lipoxygenase Inhibitors; Multigene Family; Neuroblastoma; Oxidative Stress; Pyrazoles; Sulfonamides; Tretinoin

We investigated a possible enhancement of all-trans retinoic acid (ATRA)-induced differentiation of HL-60 human myeloid leukemia cells by caffeic acid (CA), a widely distributed plant phenolic compound. Our results showed that CA, in the concentration of 13 or 52 micro M, had no or minimal influence on cell differentiation, whereas the differentiating activity of ATRA was potentiated by CA treatment. We proved, using flow cytometric detection of the CD66b surface molecule, a synergistic effect of CA: at day 10, 18.3% of CD66b-positive cells were detected after treatment with ATRA only, and 33% when CA and ATRA were combined together. NBT-assay confirmed that this additive effect of CA on ATRA-induced differentiation. Proliferating activity as assessed by MTT-assay was generally not affected by CA at given concentrations. However, cell proliferation was significantly reduced by 52 micro M CA at 96-h intervals. This effect was markedly enhanced when CA, at both concentrations, and ATRA were combined. The possibility to enhance the differentiation potential of ATRA by CA may improve outcomes in the therapy of acute promyelocytic leukemia.

Topics: Antigens, CD; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Caffeic Acids; Cell Adhesion Molecules; Cell Differentiation; Cell Proliferation; Coloring Agents; Dose-Response Relationship, Drug; Drug Synergism; Flow Cytometry; GPI-Linked Proteins; HL-60 Cells; Humans; Immunophenotyping; Leukemia, Promyelocytic, Acute; Models, Chemical; Tetrazolium Salts; Thiazoles; Time Factors; Tretinoin

We have studied the effects of lipoxygenase inhibition and metabolite addition of HL-60 cells induced to differentiate. When HL-60 are induced by dimethyl sulfoxide (DMSO) in the presence of an inhibitor of lipoxygenase, caffeic acid, there is a marked change from the expected phenotype of mature granulocytes to a population composed predominantly of mature monocytes. (DMSO alone: 54% granulocytes, 10% monocytes; DMSO + caffeic acid: 23% granulocytes, 53% monocytes.) Addition of leukotriene D4 to DMSO-induced, caffeic acid-inhibited cultures resulted in a dose-dependent recovery of the granulocyte phenotype. Addition of lipoxygenase inhibitors to phorbol ester-treated HL-60 cells did not alter the expected monocytic differentiation. These results support a role for leukotriene D4 in the regulation of granulocyte differentiation of HL-60 cells induced with DMSO.

Topics: Caffeic Acids; Cell Adhesion; Cell Differentiation; Dimethyl Sulfoxide; Epoprostenol; Granulocytes; Histocytochemistry; Humans; In Vitro Techniques; Lipoxygenase Inhibitors; Monocytes; SRS-A; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured

Chlorogenic acid (3-O-caffeoylquinic acid) inhibited haematin- and haemoglobin-catalysed retinoic acid 5,6-epoxidation. Some other phenol compounds (caffeic acid and 4-hydroxy-3-methoxybenzoic acid) also showed inhibitory effects on the haematin- and haemoglobin-catalysed epoxidation, but salicylic acid did not. Of the above compounds, caffeic acid and chlorogenic acid were potent inhibitors compared with the other two, suggesting that the o-hydroquinone moiety of chlorogenic acid and caffeic acid is essential to the inhibition of the epoxidation. Although caffeic acid inhibited retinoic acid 5,6-epoxidation requiring the consumption of O2, formation of retinoic acid radicals was not inhibited on the addition of caffeic acid to the incubation mixture. The above results suggest that caffeic acid does not inhibit the formation of retinoic acid radicals but does inhibit the step of conversion of retinoic acid radical into the 5,6-epoxide.

Topics: Caffeic Acids; Chlorogenic Acid; Chromatography, High Pressure Liquid; Electron Spin Resonance Spectroscopy; Free Radicals; Heme; Hemin; Hemoglobins; Humans; Kinetics; Phenols; Tretinoin