Matsunaga Hiroko, Tanaka Shinji, Aihara Arihiro, Ogawa Kousuke, Matsumura Satoshi, Ban Daisuke, Ochiai Takanori, Irie Takumi, Kudo Atsushi, Nakamura Noriaki, Arii Shigeki, Tanabe Minoru
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Ann Surg Oncol. 2015 Sep;22(9):3079-86. doi: 10.1245/s10434-014-4292-3. Epub 2014 Dec 19.
Effective therapeutic combinations targeting the oncogenic pathway still are unknown in human hepatocellular carcinoma (HCC). The authors previously identified aberrant expression of aurora B kinase as the independent predictor for the lethal recurrence of HCC, showing that AZD1152 induced in vitro and in vivo apoptosis with polyploidy in human HCC cells. In this preclinical study, the combined effects of molecular-targeted therapies were evaluated based on the cellular response of aurora B inhibition.
This study analyzed the expression of Bcl-2 family proteins in polyploidization induced by AZD1152 and the in vitro synergistic effects of AZD1152 with control of the Bcl-2 family pathway in human HCC cells. The in vivo effects of the combination therapy targeting the specific molecules were evaluated using subcutaneous tumor xenograft models.
The findings showed that Bcl-xL was specifically overexpressed in AZD1152-induced polyploid HCC cells. The combination of AZD1152 followed by Bcl-xL/2 inhibitor ABT263 induced synergistically cellular apoptosis (p < 0.001) and growth inhibition (p < 0.0001). Interestingly, the reverse sequential administration of AZD1152 combined with pretreatment of ABT263 was less effective than the original one. In vivo studies using tumor xenografts of human HCC cells showed that combination therapy of ABT263 after AZD1152 pretreatment induced significant intratumoral apoptosis (p < 0.05) and remarkable anti-tumor effects (p < 0.05) without a severe adverse effect compared with the monotherapy.
Based on Bcl-xL overexpression in polyploidy induced by aurora B inhibition, the rationale for therapeutic combinations targeting aurora B and Bcl-xL was demonstrated in the authors' preclinical studies, leading to a promising novel approach for the mechanism-based treatment of human HCC.
在人类肝细胞癌（HCC）中，针对致癌途径的有效治疗组合仍然未知。作者之前已确定极光B激酶的异常表达是HCC致死性复发的独立预测指标，表明AZD1152可在体外和体内诱导人HCC细胞发生多倍体凋亡。在这项临床前研究中，基于极光B抑制的细胞反应评估了分子靶向治疗的联合效果。
本研究分析了AZD1152诱导的多倍体形成过程中Bcl-2家族蛋白的表达，以及AZD1152与人HCC细胞中Bcl-2家族途径调控的体外协同效应。使用皮下肿瘤异种移植模型评估了靶向特定分子的联合治疗的体内效果。
研究结果显示，Bcl-xL在AZD1152诱导的多倍体HCC细胞中特异性过表达。AZD1152联合Bcl-xL/2抑制剂ABT263可协同诱导细胞凋亡（p<0.001）和生长抑制（p<0.0001）。有趣的是，AZD1152与ABT263预处理的反向序贯给药效果不如原始给药方式。使用人HCC细胞肿瘤异种移植进行的体内研究表明，与单药治疗相比，AZD1152预处理后给予ABT263的联合治疗可诱导显著的瘤内凋亡（p<0.05）和显著的抗肿瘤效果（p<0.05），且无严重不良反应。
基于极光B抑制诱导的多倍体中Bcl-xL的过表达，作者的临床前研究证明了靶向极光B和Bcl-xL的治疗组合的基本原理，为基于机制的人类HCC治疗带来了一种有前景的新方法。
