Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts

Chiu, M. et al. (2014) Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts. British Journal of Cancer, 111(6), pp. 1159-1167. (doi: 10.1038/bjc.2014.425) (PMID:25072259) (PMCID:PMC4453854)

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Abstract

Background: A subset of human hepatocellular carcinomas (HCC) exhibit mutations of β-catenin gene CTNNB1 and overexpress Glutamine synthetase (GS). The CTNNB1-mutated HCC cell line HepG2 is sensitive to glutamine starvation induced in vitro with the antileukemic drug Crisantaspase and the GS inhibitor methionine-L-sulfoximine (MSO). Methods: Immunodeficient mice with subcutaneous xenografts of the CTNNB1-mutated HCC cell lines HepG2 and HC-AFW1 were treated with Crisantaspase and/or MSO, and tumour growth was monitored. At the end of treatment, tumour weight and histology were assessed. Serum and tissue amino acids were determined by HPLC. Gene and protein expression were estimated with RT-PCR and western blot and GS activity with a colorimetric method. mTOR activity was evaluated from the phosphorylation of p70S6K1. Results: Crisantaspase and MSO depleted serum glutamine, lowered glutamine in liver and tumour tissue, and inhibited liver GS activity. HepG2 tumour growth was significantly reduced by either Crisantaspase or MSO, and completely suppressed by the combined treatment. The combined treatment was also effective against xenografts of the HC-AFW1 cell line, which is Crisantaspase resistant in vitro. Conclusions: The combination of Crisantaspase and MSO reduces glutamine supply to CTNNB1-mutated HCC xenografts and hinders their growth.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tardito, Dr Saverio
Authors: Chiu, M., Tardito, S., Pillozzi, S., Arcangeli, A., Armento, A., Uggeri, J., Missale, G., Bianchi, M.G., Barilli, A., Dall'Asta, V., Campanini, N., Silini, E.M., Fuchs, J., Armeanu-Ebinger, S., and Bussolati, O.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:British Journal of Cancer
Publisher:Cancer Research UK
ISSN:0007-0920
ISSN (Online):1532-1827
Published Online:29 July 2014
Copyright Holders:Copyright © 2014 Cancer Research UK
First Published:First published in British Journal of Cancer 111(6): 1159-1167
Publisher Policy:Reproduced under a Creative Commons License

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