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Effects of ellagic acid in human neuroblastoma cells
Karlstad University, Faculty of Health, Science and Technology (starting 2013), Department of Health Sciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A diet rich in polyphenols has been proposed to have beneficial health effects and to reduce risk of disease. Ellagic acid, a polyphenol common in red berries and pomegranates, has potential anti-tumorigenic effects that make it interesting to further study in different cancer cell systems.

Neuroblastoma is a childhood cancer that arises during development of the peripheral nervous system. Neuroblastoma, being an embryonal tumor, show loss of function of genes controlling differentiation and apoptosis. Neuroblastoma is a heterogenic tumor disease, and highly malignant neuroblastomas are difficult to treat despite different treatment modalities, identifying a need for new and combinatory treatments. A common model for human neuroblastoma is the SH-SY5Y cell line resembling immature neuroblasts that can be differentiated in vitro with several agents including the phorbol ester 12-O-tetradecanoylphorbol-13-acetate and the vitamin A-derivative all-trans retinoic acid.

Here, the effect of ellagic acid on proliferation, cell detachment and apoptosis in non-differentiated and in vitro-differentiated SH-SY5Y cells were studied with the aim of identifying cellular target mechanisms and a possible therapeutic potential for ellagic acid.

In non-differentiated cells, ellagic acid reduced cell number, inhibited cell cycle activity, and induced cell detachment and apoptosis. Apoptosis was partly mediated by the intrinsic pathway. 12-O-tetradecanoylphorbol-13-acetate and all-trans retinoic acid both induced morphological differentiation, while only the latter induced G0/G1-arrest. Single-cell analysis revealed that 12-O-tetradecanoylphorbol-13-acetate-treated cells continued cycling during neuritogenesis while these two read-outs were mutually exclusive in all-trans retinoic acid-treated cells. 12-O-tetradecanoylphorbol-13-acetate- and especially all-trans retinoic acid-differentiated cells showed lower sensitivity to ellagic acid-dependent cell detachment and apoptosis.

Place, publisher, year, edition, pages
Karlstad: Karlstads universitet, 2013. , 74 p.
Series
Karlstad University Studies, ISSN 1403-8099 ; 2013:48
Keyword [en]
polyphenols, ellagic acid, neuroblastoma, SH-SY5Y cells, differentiation, proliferation, apoptosis, cell adhesion
National Category
Medical and Health Sciences
Research subject
Biomedical Sciences
Identifiers
URN: urn:nbn:se:kau:diva-29905ISBN: 978-91-7063-526-7 (print)OAI: oai:DiVA.org:kau-29905DiVA: diva2:661066
Public defence
2013-11-29, Ljungbergsalen, 21A 244, Universitetsgatan 2, 651 88 Karlstad, Karlstad, 10:15 (English)
Opponent
Supervisors
Note

Artikel 4 ("Altered sensitivity...") ingick som manuskript i avhandlingen, nu publicerad.

Available from: 2013-11-08 Created: 2013-10-24 Last updated: 2016-02-24Bibliographically approved
List of papers
1. Proliferation in morphologically differentiated SH-SY5Y human neuroblastoma cells
Open this publication in new window or tab >>Proliferation in morphologically differentiated SH-SY5Y human neuroblastoma cells
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Biomedical Sciences
Identifiers
urn:nbn:se:kau:diva-29904 (URN)
Available from: 2013-10-24 Created: 2013-10-24 Last updated: 2017-12-07Bibliographically approved
2. Effect of ellagic acid on proliferation, cell adhesion and apoptosis in SH-SY5Y human neuroblastoma cells
Open this publication in new window or tab >>Effect of ellagic acid on proliferation, cell adhesion and apoptosis in SH-SY5Y human neuroblastoma cells
2009 (English)In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 63, no 4, 254-261 p.Article in journal (Refereed) Published
Abstract [en]

Ellagic acid, a polyphenolic compound found in berries, fruits and nuts, has been shown to possess growth-inhibiting and apoptosis promoting activities in cancer cell lines in vitro. The objective of this study was to investigate the effect of ellagic acid in human neuroblastoma SH-SY5Y cells. In cultures of SH-SY5Y cells incubated with ellagic acid, time- and concentration-dependent inhibitory effects on cell number were demonstrated.Ellagic acid induced cell detachment, decreased cell viability and induced apoptosis as measured by DNA strand breaks. Ellagic acid-induced alterations in cell cycle were also observed. Simultaneous treatment with all-trans retinoic acid did not rescue the cells from ellagic acid effects. Furthermore, the results suggested that pre-treatment with all-trans retinoic acid to induce differentiation and cell cycle arrest did not rescue the cells from ellagic acid-induced cell death.

Keyword
Ellagic acid, Apoptosis, Neuroblastoma
National Category
Biological Sciences Biological Sciences
Research subject
Biomedical Sciences
Identifiers
urn:nbn:se:kau:diva-9905 (URN)10.1016/j.biopha.2008.07.093 (DOI)
Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-12-07Bibliographically approved
3. Ellagic acid induces a dose- and time-dependent depolarization of mitochondria and activation of caspase-9 and -3 in human neuroblastoma cells
Open this publication in new window or tab >>Ellagic acid induces a dose- and time-dependent depolarization of mitochondria and activation of caspase-9 and -3 in human neuroblastoma cells
Show others...
2014 (English)In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 68, no 1, 129-135 p.Article in journal (Refereed) Published
Abstract [en]

The polyphenol ellagic acid is found in many natural food sources and has been proposed as a candidate compound for clinical applications due to its anti-oxidative capacity and as a potential anti-tumorigenic compound. The objective of the present study was to evaluate the sensitivity to and possible apoptosis mechanism induced by ellagic acid in neuronal tumor cells. As a model the human neuroblastoma SH-SY5Y cell line was used. The methods applied were bright field and phase contrast microscopy, XTT- and LDH-assays, western blot, and flow cytometric analysis of DNA degradation and mitochondrial membrane potential. Ellagic acid treatment was found to induce a reduction in cell number preceded by alterations of the mitochondrial membrane potential and activation of caspase-9 and -3, DNA-fragmentation and cell death by apoptosis. The apoptotic cell death studied was not due to anoikis since it was significant in the adherent fraction of the cells. We conclude that ellagic acid induces dose- and time-dependent apoptosis, at least partly by the mitochondrial pathway, in an embryonal neuronal tumor cell system. This finding is in agreement with previously reported data on adult carcinoma cells thus suggesting a more general effect of ellagic acid on tumor cells.

Place, publisher, year, edition, pages
Elsevier, 2014
National Category
Medical and Health Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:kau:diva-29599 (URN)10.1016/j.biopha.2013.08.010 (DOI)000332448400019 ()24051122 (PubMedID)
Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2017-08-15Bibliographically approved
4. Altered sensitivity to ellagic acid in neuroblastoma cells undergoing differentiation with 12-0-tetradecanoylphorbol-13-acetate and all-trans retinoic acid
Open this publication in new window or tab >>Altered sensitivity to ellagic acid in neuroblastoma cells undergoing differentiation with 12-0-tetradecanoylphorbol-13-acetate and all-trans retinoic acid
Show others...
2015 (English)In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 76, 39-45 p.Article in journal (Refereed) Published
Abstract [en]

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 SubG(1)-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.

Keyword
Ellagic acid, Cell adhesion, Apoptosis, Neuroblastoma, Differentiation
National Category
Basic Medicine
Research subject
Biomedical Sciences
Identifiers
urn:nbn:se:kau:diva-29903 (URN)10.1016/j.biopha.2015.10.008 (DOI)000367541500007 ()
Available from: 2013-10-24 Created: 2013-10-24 Last updated: 2017-12-07Bibliographically approved

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