Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts.
Glutamine depletion by crisantaspase hinders the growth of human hepatocellular carcinoma xenografts.
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DOI：
10.1038/bjc.2014.425
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发表时间：
2014-09-09
影响因子：
8.8
通讯作者：
Bussolati, O.
中科院分区：
文献类型：
--
作者：
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.;Bussolati, O.
关键词：
一部分人类肝细胞癌 (HCC) 表现出 β-连环蛋白基因 CTNNB1 突变并过度表达谷氨酰胺合成酶 (GS)。 CTNNB1 突变的 HCC 细胞系 HepG2 对体外用抗白血病药物 Crisantaspase 和 GS 抑制剂蛋氨酸-L-亚磺酰亚胺 (MSO) 诱导的谷氨酰胺饥饿敏感。用 Crisantaspase 和/或 MSO 处理皮下移植有 CTNNB1 突变 HCC 细胞系 HepG2 和 HC-AFW1 的免疫缺陷小鼠，并监测肿瘤生长。治疗结束时，评估肿瘤重量和组织学。通过HPLC测定血清和组织氨基酸。通过 RT-PCR 和蛋白质印迹评估基因和蛋白质表达，并通过比色法评估 GS 活性。 mTOR 活性通过 p70S6K1 的磷酸化进行评估。 Crisantaspase 和 MSO 消耗血清谷氨酰胺，降低肝脏和肿瘤组织中的谷氨酰胺，并抑制肝脏 GS 活性。 Crisantaspase 或 MSO 显着减少 HepG2 肿瘤生长，并通过联合治疗完全抑制。联合治疗对 HC-AFW1 细胞系的异种移植也有效，该细胞系在体外具有 Crisantaspase 耐药性。 Crisantaspase 和 MSO 的组合减少了 CTNNB1 突变的 HCC 异种移植物的谷氨酰胺供应，并阻碍其生长。
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). 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. 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. The combination of Crisantaspase and MSO reduces glutamine supply to CTNNB1-mutated HCC xenografts and hinders their growth.
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影响因子：
4.1
作者：
Aslanian, AM;Kilberg, MS
通讯作者：
Kilberg, MS
影响因子：
8
作者：
Cadoret, A;Ovejero, C;Perret, C
通讯作者：
Perret, C
影响因子：
25.7
作者：
Behari, Jaideep;Zeng, Gang;Monga, Satdarshan P. S.
通讯作者：
Monga, Satdarshan P. S.
影响因子：
13.5
作者：
Beyoglu, Diren;Imbeaud, Sandrine;Maurhofer, Olivier;Bioulac-Sage, Paulette;Zucman-Rossi, Jessica;Dufour, Jean-Francois;Idle, Jeffrey R.
通讯作者：
Idle, Jeffrey R.
DOI：
10.1056/nejmoa0804525
发表时间：
2008-11-06
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hoshida Y;Villanueva A;Kobayashi M;Peix J;Chiang DY;Camargo A;Gupta S;Moore J;Wrobel MJ;Lerner J;Reich M;Chan JA;Glickman JN;Ikeda K;Hashimoto M;Watanabe G;Daidone MG;Roayaie S;Schwartz M;Thung S;Salvesen HB;Gabriel S;Mazzaferro V;Bruix J;Friedman SL;Kumada H;Llovet JM;Golub TR
通讯作者：
Golub TR