A CD13 inhibitor, ubenimex, synergistically enhances the effects of anticancer drugs in hepatocellular carcinoma.
A CD13 inhibitor, ubenimex, synergistically enhances the effects of anticancer drugs in hepatocellular carcinoma.
复制标题
DOI：
10.3892/ijo.2016.3496
复制
发表时间：
2016-07
影响因子：
5.2
通讯作者：
Mori M
中科院分区：
文献类型：
--
作者：
Yamashita M;Wada H;Eguchi H;Ogawa H;Yamada D;Noda T;Asaoka T;Kawamoto K;Gotoh K;Umeshita K;Doki Y;Mori M
据报道，癌症干细胞（CSC）参与对化疗/放疗的抵抗。我们先前报道了CD 13既是CSCs的标志物，也是HCC的候选治疗靶点。在本研究中，我们探讨了联合治疗的抗肿瘤作用，其中乌苯美司，一种CD 13抑制剂，与传统的抗癌药物，氟尿嘧啶（5-FU），顺铂（CDDP），阿霉素（DXR）和索拉非尼（SOR），我们阐明了这些联合治疗的机制。我们评估了在人肝癌细胞系HuH 7和PLC/PRF/5中用抗癌药物治疗前后以及有或没有乌苯美司治疗前后CD 13表达的变化。用等效线分析法测定了抗癌药物与乌苯美司之间的相互作用。我们分析了细胞周期、凋亡和细胞内活性氧（ROS）水平，以探讨联合治疗的机制。在两种细胞系中，单独暴露于每种抗癌药物72小时后，CD 13的表达增加（P<0.05），并且CD 13的表达随着乌苯美司给药而降低（P<0.05）。等辐射图分析表明，乌苯美司与5-FU、CDDP、DXR有协同作用，与SOR有相加作用。细胞周期分析显示乌苯美司降低了G 0/G1期细胞的比例。乌苯美司通过增加细胞凋亡和细胞内ROS水平增强5-FU、CDDP和DXR的作用。在联合治疗中，乌苯美司协同增强5-FU、CDDP和DXR对HCC细胞系细胞周期调节和凋亡诱导的抗肿瘤作用。乌苯美司的作用是由于增加细胞内ROS水平。
Cancer stem cells (CSCs) were reported to be involved in resistance to chemo/radiation therapy. We previously reported that CD13 was both a marker of CSCs and a candidate therapeutic target in HCC. In the present study, we explored the antitumor effect of a combined therapy, where ubenimex, a CD13 inhibitor, was combined with conventional anticancer drugs, fluorouracil (5-FU), cisplatin (CDDP), doxorubicin (DXR) and sorafenib (SOR), and we elucidated the mechanism of these combination therapies. We evaluated changes in the expression of CD13 before and after treatment with anticancer drugs and with or without ubenimex in the human HCC cell lines HuH7 and PLC/PRF/5. The interactions between the anticancer drugs and ubenimex were determined with isobologram analyses. We analyzed cell cycle, apoptosis, and intracellular reactive oxygen species (ROS) levels to explore the mechanisms of the combination therapies. In both cell lines, the expression of CD13 increased after a 72-h exposure to each anticancer drug alone (P<0.05), and the expression of CD13 decreased with ubenimex administration (P<0.05). Isobologram analyses indicated that ubenimex had synergistic effects with 5-FU, CDDP and DXR, and an additive effect with SOR. Cell cycle analyses showed that ubenimex decreased the proportion of cells in G0/G1. Ubenimex enhanced the effects of 5-FU, CDDP and DXR by increasing apoptosis and intracellular ROS levels. In combination therapies, ubenimex synergistically enhanced the antitumor effects of 5-FU, CDDP and DXR on cell cycle regulation and apoptosis induction in HCC cell lines. The effects of ubenimex were due to increased intracellular ROS levels.