Antitumor activity of the microtubule inhibitor MBRI-001 against human hepatocellular carcinoma as monotherapy or in combination with sorafenib
Antitumor activity of the microtubule inhibitor MBRI-001 against human hepatocellular carcinoma as monotherapy or in combination with sorafenib
复制标题
微管抑制剂 MBRI-001 单独治疗或与索拉非尼联合治疗对人肝细胞癌的抗肿瘤活性
DOI：
10.1007/s00280-018-3547-2
复制
发表时间：
2018-05-01
影响因子：
3
通讯作者：
Li, Wenbao
中科院分区：
文献类型：
--
作者：
Deng, Mengyan;Li, Linna;Li, Wenbao
目的MBRI-001是一种新的普那布林衍生物。本研究旨在探讨MBRI-001单药或与索拉非尼联合应用对人肝癌细胞株HCCLM 3和Bel-7402的抑制作用。MTT法检测MBRI-001的抗增殖活性。免疫荧光法检测微管形态学变化。流式细胞仪检测细胞周期。RT-qPCR和Western blotting检测细胞周期蛋白B1（CCNB 1）的表达。结果MBRI-001对人肝癌细胞株HCCLM 3和Bel-7402的抗增殖活性优于普那布林。MBRI-001抑制微管的形成，并诱导G2/M期阻滞，同时下调CCNB 1。在原位小鼠模型中，MBRI-001显著抑制HCCLM 3的生长，并观察到肿瘤的凋亡和坏死。MBRI-001与索拉非尼联合应用对小鼠皮下移植瘤的抑瘤率为72.0%，高于MBRI-001或索拉非尼单药的40.7%和47.7%.Conclusion MBRI-001对微管和人肝癌的抑制作用优于普那布林。MBRI-001与索拉非尼联合治疗肝癌具有较好的抗肿瘤作用，为今后肝癌的治疗提供了新的思路。
PurposeMBRI-001 is a novel synthetic derivative of plinabulin. In this study, our purpose is to investigate the inhibition effects of MBRI-001 on human hepatocellular carcinoma as monotherapy or in combination with sorafenib.MethodsHCCLM3 and Bel-7402 cell lines were used for activity evaluation in vitro. The anti-proliferative activity of MBRI-001 was assessed by MTT assay. The morphological change of microtubules was determined by immunofluorescence assay. The cell cycle was measured by flow cytometer. The expression of cyclin B1 (CCNB1) was analyzed by RT-qPCR and western blotting assays. The antitumor activities in vivo were evaluated with human HCC xenograft mice model.ResultsOur data demonstrated that MBRI-001 had better anti-proliferative activities than that of plinabulin against HCCLM3 and Bel-7402 cell lines. MBRI-001 inhibited the formation of microtubules and induced G2/M arrest with the downregulation of CCNB1. In vivo orthotopic mice model demonstrated that MBRI-001 significantly inhibited the growth of HCCLM3 with the apoptosis and necrosis observed in tumor. The combination treatment of MBRI-001 with sorafenib in subcutaneous mice model exhibited a higher antitumor inhibition rate at 72.0%, in comparison with MBRI-001 or sorafenib as monotherapy at 40.7% or 47.7%, respectively.ConclusionMBRI-001 had better inhibition effects on microtubules and human hepatocellular carcinoma than that of plinabulin. The combination treatment of MBRI-001 and sorafenib exhibited a higher antitumor effect, which could provide a new strategy to treat HCC in the future.