Lookup NU author(s): Dr Lindi Chen,
Professor John Lunec,
Professor Deborah Tweddle
This is the final published version of an article that has been published in its final definitive form by Spandidos Publications, 2018.
For re-use rights please refer to the publisher's terms and conditions.
Cell lines established from the TH-MYCN transgenic murine model of neuroblastoma are a valuable preclinical, immunocompetent, syngeneic model of neuroblastoma, for which knowledge of their p53 pathway status is important. Trp53 status and functional response to Nutlin-3 and ionising radiation (IR) were determined in 6 adherent TH-MYCN transgenic cell lines using Sanger sequencing, immunoblotting and flow cytometry. Sensitivity to structurally diverse MDM2 inhibitors (Nutlin-3, MI-63, RG7388 and NDD0005) were determined using XTT proliferations assays. 2/6 cell lines were Trp53 homozygous mutant (NHO2A and 844MYCN+/+) and 1/6 (282MYCN+/-) was Trp53 heterozygous mutant. For 1/6 cell lines (NHO2A), DNA from the corresponding primary tumour was found to be Trp53 wt. In all cases, the presence of a mutation was consistent with aberrant p53 signalling in response to Nutlin-3 and IR. In comparison to TP53 wt human neuroblastoma cells, Trp53 wt murine control and TH-MYCN cell lines were significantly less sensitive to growth inhibition mediated by MI-63 and RG7388. These murine Trp53 wt and mutant TH-MYCN cell lines are useful syngeneic immunocompetent neuroblastoma models, the former to test p53-dependent therapies in combination with immunotherapies, such as anti-GD2, and the latter as models of chemoresistant relapsed neuroblastoma when aberrations in the p53 pathway are more common. The spontaneous development of Trp53 mutations in 3 cell lines from TH-MYCN mice may have arisen from MYCN oncogenic driven and/or ex-vivo selection. The identified species-dependent selectivity of MI-63 and RG7388 should be considered when interpreting in vivo toxicity studies of MDM2 inhibitors.
Author(s): Chen L, Esfandiari A, Reaves W, Vu A, Hogarty MD, Lunec J, Tweddle DA
Publication type: Article
Publication status: Published
Journal: International Journal of Oncology
Print publication date: 01/03/2018
Online publication date: 31/01/2018
Acceptance date: 12/12/2017
Date deposited: 08/02/2018
ISSN (print): 1019-6439
ISSN (electronic): 1791-2423
Publisher: Spandidos Publications
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