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Increasing the intracellular availability of all-trans retinoic acid in neuroblastoma cells

Lookup NU author(s): Dr Jane Renwick, Professor Alan Boddy, Dr Chris Redfern, Professor Andrew Pearson, Professor Gareth Veal

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Abstract

Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acttretin (50 μM) or R116010 (1 or 10 μM) in combination with either 10 μM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma. © 2005 Cancer Research UK.


Publication metadata

Author(s): Armstrong, J., Ruiz, M., Boddy, A. V., Redfern, C., Pearson, A. D. J., Veal, G. J.

Publication type: Article

Publication status: Published

Journal: British Journal of Cancer

Year: 2005

Volume: 92

Issue: 4

Pages: 696-704

Print publication date: 28/02/2005

ISSN (print): 0007-0920

ISSN (electronic): 1532-1827

URL: http://dx.doi.org/10.1038/sj.bjc.6602398

DOI: 10.1038/sj.bjc.6602398

PubMed id: 15714209


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