The combination of proteasome inhibitors bortezomib and gambogic acid triggers synergistic cytotoxicity in vitro but not in vivo
The combination of proteasome inhibitors bortezomib and gambogic acid triggers synergistic cytotoxicity in vitro but not in vivo
复制标题
蛋白酶体抑制剂硼替佐米和藤黄酸的组合在体外触发协同细胞毒性，但在体内不触发
DOI：
10.1016/j.toxlet.2013.11.021
复制
发表时间：
2014-01-30
影响因子：
3.5
通讯作者：
Liu, Jinbao
中科院分区：
文献类型：
--
作者：
Liu, Ningning;Huang, Hongbiao;Liu, Jinbao
以蛋白酶体抑制剂为基础的联合治疗已被报道为一种有效的癌症治疗方法。我们最近的研究表明，天然化合物藤黄酸（GA）是一种组织特异性蛋白酶体抑制剂，与硼替佐米（Bor）相当，在体外和体内都能使恶性细胞对蛋白酶体抑制剂MG132/MG262致敏。本研究的目的是进一步扩展我们的研究，将GA与临床使用的蛋白酶体抑制剂Bor联合使用，测试它们对人肝癌HepG2和小鼠肝癌H22细胞的联合疗效。GA和Bor协同诱导人HepG2和小鼠H22细胞的细胞毒性和细胞死亡，加速HepG2癌细胞的蛋白酶体抑制、内质网（ER）应激和caspase激活。然而，出乎意料的是，在H22异体移植和HepG2异种移植肿瘤模型中，GA并没有增强甚至拮抗bor诱导的肿瘤生长抑制。这些结果表明，GA在体外增加了Bor的活性，但限制了Bor在体内的功效。我们建议在给患者使用这些药物时避免GA和Bor的联合使用。2013爱思唯尔爱尔兰有限公司版权所有。
The proteasome inhibitor-based combinational therapy has been reported to be an efficient cancer treatment. Our recent studies demonstrated that the natural compound gambogic acid (GA) is a tissue-specific proteasome inhibitor, comparable to bortezomib (Bor), and sensitizes malignant cells to the proteasome inhibitor MG132/MG262 both in vitro and in vivo. The aim of this study was to further extend our investigation by combining GA with the clinically used proteasome inhibitor Bor to test their combined efficacy against human hepatoma HepG2 and mouse hepatoma H22 cells. GA and Bor synergistically induced cytotoxicity and cell death in human HepG2 and mouse H22 cells, and accelerated proteasome inhibition, endoplasmic reticulum (ER) stress and caspase activation in HepG2 cancer cells. However, unexpectedly, GA did not enhance or even antagonized Bor-induced tumor growth inhibition in H22 allograft and HepG2 xenograft tumor models. These findings demonstrated that GA increased Bor activity in vitro but limited the efficacy of Bor in vivo. We suggest that the combination of GA and Bor be avoided when administering these drugs to patients. (C) 2013 Elsevier Ireland Ltd. All rights reserved.