title: Altered sensitivity to ellagic acid in neuroblastoma cells undergoing differentiation with 12-O-tetradecanoylphorbol-13-acetate and all-trans retinoic acid.
abstract: Ellagic acid has previously been reported to induce reduced proliferation and activation of apoptosis in several tumor cell lines including our own previous data from non-differentiated human neuroblastoma SH-SY5Y cells. The aim of this study was now to investigate if in vitro differentiation with the phorbol ester 12-O- tetradecanoylphorbol-13-acetate or the vitamin A derivative all-trans retinoic acid altered the sensitivity to ellagic acid in SH-SY5Y cells. The methods used were cell counting and LDH-assay for evaluation of cell number and cell death, flow cytometric analysis of SubG1- and TUNEL-analysis for apoptosis and western blot for expression of apoptosis-associated proteins. In vitro differentiation was shown to reduce the sensitivity to ellagic acid with respect to cell detachment, loss of viability and activation of apoptosis. The protective effect was phenotype-specific and most prominent in all-trans retinoic acid-differentiated cultures. Differentiation-dependent up-regulation of Bcl-2 and integrin expression is introduced as possible protective mechanisms. The presented data also point to a positive correlation between proliferative activity and sensitivity to ellagic-acid-induced cell detachment. In conclusion, the presented data emphasize the need to consider degree of neuronal differentiation and phenotype of neuroblastoma cells when discussing a potential pharmaceutical application of ellagic acid in tumor treatment.
authors.affiliation: Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, SE-651 88 Karlstad, Sweden.
authors.forename: Christina Fjæraa
authors.initials: CF
authors.lastname: Alfredsson
authors.affiliation: Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, SE-651 88 Karlstad, Sweden.
authors.forename: Filip
authors.initials: F
authors.lastname: Rendel
authors.affiliation: Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, SE-651 88 Karlstad, Sweden.
authors.forename: Qui-Li
authors.initials: QL
authors.lastname: Liang
authors.affiliation: Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, SE-651 88 Karlstad, Sweden.
authors.forename: Birgitta E
authors.initials: BE
authors.lastname: Sundström
authors.affiliation: Biomedical Sciences, Department of Health Sciences, Faculty of Health, Science and Technology, Karlstad University, SE-651 88 Karlstad, Sweden. Electronic address: eewa.nanberg@kau.se.
authors.forename: Eewa
authors.initials: E
authors.lastname: Nånberg
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004610:Ellagic Acid / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D016023:Integrins / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016023:Integrins; D019253:Proto-Oncogene Proteins c-bcl-2; D004610:Ellagic Acid; D014212:Tretinoin; D013755:Tetradecanoylphorbol Acetate
keywords: Apoptosis; Cell adhesion; Differentiation; Ellagic acid; Neuroblastoma