Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells.
Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells.
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DOI：
10.1038/s41419-017-0195-0
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发表时间：
2018-01-18
影响因子：
9
通讯作者：
Cervello M
中科院分区：
文献类型：
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作者：
Augello G;Modica M;Azzolina A;Puleio R;Cassata G;Emma MR;Di Sano C;Cusimano A;Montalto G;Cervello M
肝细胞癌（HCC）是一种常见的恶性肿瘤，是世界范围内日益重要的癌症死亡原因。手术、化疗和放疗仅能延长HCC患者的5年生存期6%。因此，有必要开发新的治疗方法来治疗这种疾病。口服生物可利用的蛋白酶体抑制剂MLN2238 （ixazomib）已被证明具有抗癌活性。在本研究中，我们通过体外和体内模型研究了MLN2238对HCC细胞的临床前治疗效果，并探讨了其分子作用机制。MLN2238抑制人肝癌细胞HepG2、Hep3B和SNU475的细胞活力呈时间和剂量依赖性。流式细胞术分析表明，MLN2238可诱导肝癌细胞G2/M细胞周期阻滞和细胞凋亡。细胞周期阻滞与p21和p27表达水平升高有关。通过caspase-3/7激活、PARP裂解和caspase依赖性β-catenin降解证实mln2238诱导细胞凋亡。此外，MLN2238激活肝癌细胞内质网应激基因，增加应激诱导基因核蛋白-1的表达。此外，MLN2238治疗诱导髓样细胞白血病-1 （Mcl-1）蛋白上调，Mcl-1敲低使HCC细胞对MLN2238治疗增敏，提示Mcl-1表达参与MLN2238耐药。使用新型Mcl-1小分子抑制剂A1210477也证实了这一结果。A1210477和MLN2238的联合作用决定了HCC细胞的协同抗肿瘤作用。最后，体内口服MLN2238可抑制裸鼠异种移植模型中Hep3B细胞的肿瘤生长。总之，我们的结果为HCC患者的治疗提供了新的治疗机会。
Hepatocellular carcinoma (HCC) is one of the common malignancies and is an increasingly important cause of cancer death worldwide. Surgery, chemotherapy, and radiation therapy extend the 5-year survival limit in HCC patients by only 6%. Therefore, there is a need to develop new therapeutic approaches for the treatment of this disease. The orally bioavailable proteasome inhibitor MLN2238 (ixazomib) has been demonstrated to have anticancer activity. In the present study, we investigated the preclinical therapeutic efficacy of MLN2238 in HCC cells through in vitro and in vivo models, and examined its molecular mechanisms of action. MLN2238 inhibited cell viability in human HCC cells HepG2, Hep3B, and SNU475 in a time- and dose-dependent manner. Flow cytometry analysis demonstrated that MLN2238 induced G2/M cell cycle arrest and cellular apoptosis in HCC cells. Cell cycle arrest was associated with increased expression levels of p21 and p27. MLN2238-induced apoptosis was confirmed by caspase-3/7 activation, PARP cleavage and caspase-dependent β-catenin degradation. In addition, MLN2238 activated ER stress genes in HCC cells and increased the expression of the stress-inducible gene nuclear protein-1. Furthermore, MLN2238 treatment induced upregulation of myeloid cell leukemia-1 (Mcl-1) protein, and Mcl-1 knockdown sensitized HCC cells to MLN2238 treatment, suggesting the contribution of Mcl-1 expression to MLN2238 resistance. This result was also confirmed using the novel Mcl-1 small molecule inhibitor A1210477. Association of A1210477 and MLN2238 determined synergistic antitumor effects in HCC cells. Finally, in vivo orally administered MLN2238 suppressed tumor growth of Hep3B cells in xenograft models in nude mice. In conclusion, our results offer hope for a new therapeutic opportunity in the treatment of HCC patients.
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影响因子：
4.6
作者：
Dabiri Y;Kalman S;Gürth CM;Kim JY;Mayer V;Cheng X
通讯作者：
Cheng X
影响因子：
4.6
作者：
Li H;Chen Z;Hu T;Wang L;Yu Y;Zhao Y;Sun W;Guan S;Pang JC;Woodfield SE;Liu Q;Yang J
通讯作者：
Yang J
影响因子：
9.7
作者：
Fan, Fengjuan;Tonon, Giovanni;Podar, Klaus
通讯作者：
Podar, Klaus
影响因子：
--
作者：
Cusimano A;Puleio R;D'Alessandro N;Loria GR;McCubrey JA;Montalto G;Cervello M
通讯作者：
Cervello M
影响因子：
9
作者：
通讯作者：
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