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Influence of isomerisation on the growth inhibitory effects and cellular activity of 13-cis and all-trans retinoic acid in neuroblastoma cells

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

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Abstract

Treatment with 13-cis retinoic acid (13-cis RA) has been shown to significantly improve the clinical outcome of children with high-risk neuroblastoma. Despite the large number of studies investigating the cellular effects of retinoids in neuroblastoma cells, the influence of RA isomerisation and the factors that determine the extent of RA isomerisation and uptake are unknown. The aim of this study was to establish the extent of extra- and intracellular isomerisation of 13-cis RA and all-trans retinoic acid (ATRA) in neuroblastoma cell lines, and to investigate the influence of isomerisation on their growth inhibitory effects and on the regulation of expression of cellular retinoic acid binding protein II (CRABP II) and RAR-β. Limited extracellular isomerisation was observed up to 72hr after incubation of four neuroblastoma cell lines with 10μM 13-cis RA or ATRA. The retinoic acid isomer present initially in the medium accounted for >75% of extracellular retinoid exposure. By contrast, incubation with 13-cis RA resulted in intracellular levels of ATRA comparable to those of 13-cis RA. This degree of intracellular isomerisation was not observed after ATRA incubations, with 13-cis RA accounting for <10% of total intracellular retinoids. No differences were observed in the sensitivity of three N-type neuroblastoma cell lines to either 13-cis RA (IC50: 11.2-13.9μM) or ATRA (IC50: 12.9-14.4μM), despite 10-fold differences in intracellular retinoid levels. A decrease in sensitivity to 13-cis RA (IC50 = 137μM), as compared to ATRA (IC50 = 41μM), was observed in the S-type cell line SH S EP. RAR-β was induced in a dose-dependent manner in SH SY 5Y cells following incubation with ATRA, whereas a weaker and delayed induction was observed with 13-cis RA. Similarly, incubation with ATRA resulted in a greater induction of CRABP II in these cells. In summary, these results indicate either an intracellular conversion of 13-cis RA to ATRA or a selective uptake of ATRA and suggest that this may mediate the differential activity of 13-cis RA in neuroblastoma cell subtypes. © 2002 Elsevier Science Inc. All rights reserved.


Publication metadata

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

Publication type: Article

Publication status: Published

Journal: Biochemical Pharmacology

Year: 2002

Volume: 63

Issue: 2

Pages: 207-215

Print publication date: 15/01/2002

ISSN (print): 0006-2952

ISSN (electronic): 1873-2968

URL: http://dx.doi.org/10.1016/S0006-2952(01)00844-9

DOI: 10.1016/S0006-2952(01)00844-9

PubMed id: 11841795


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