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A CD13 inhibitor, ubenimex, synergistically enhances the effects of anticancer drugs in hepatocellular carcinoma

细胞凋亡 药理学 细胞周期 阿霉素 顺铂 癌症研究 细胞培养 肝细胞癌 索拉非尼 细胞生长 细胞周期检查点 活性氧 化学 医学 化疗 生物 内科学 生物化学 遗传学
作者
Masafumi Yamashita,Hiroshi Wada,Hidetoshi Eguchi,Hisataka Ogawa,Daisaku Yamada,Takehiro Noda,Tadafumi Asaoka,Koichi Kawamoto,Kunihito Gotoh,Koji Umeshita,Yuichiro� Doki,Masaki Mori
出处
期刊:International Journal of Oncology [Spandidos Publishing]
卷期号:49 (1): 89-98 被引量:62
标识
DOI:10.3892/ijo.2016.3496
摘要

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.
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