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2014 ; 111
(6
): 1159-67
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Glutamine depletion by crisantaspase hinders the growth of human hepatocellular
carcinoma xenografts
#MMPMID25072259
Chiu M
; Tardito S
; Pillozzi S
; Arcangeli A
; Armento A
; Uggeri J
; Missale G
; Bianchi MG
; Barilli A
; Dall'Asta V
; Campanini N
; Silini EM
; Fuchs J
; Armeanu-Ebinger S
; Bussolati O
Br J Cancer
2014[Sep]; 111
(6
): 1159-67
PMID25072259
show ga
BACKGROUND: A subset of human hepatocellular carcinomas (HCC) exhibit mutations
of ?-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.
|*Glutamine/analysis/blood
[MESH]
|Animals
[MESH]
|Antineoplastic Agents/therapeutic use
[MESH]
|Asparaginase/*pharmacology/*therapeutic use
[MESH]