Sun Zhi-Peng, Zhang Jian, Shi Li-Hong, Zhang Xiu-Rong, Duan Yu, Xu Wen-Fang, Dai Gong, Wang Xue-Jian
Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
Department of Medical Chemistry, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
Biomed Pharmacother. 2015 Dec;76:65-72. doi: 10.1016/j.biopha.2015.10.023. Epub 2015 Nov 10.
Aminopeptidase N (APN, also known as CD13) is involved in cellular processes of various types of tumors and a potential anti-cancer therapeutic target. Here, we report the effect of an APN inhibitor 4cc in enhancing sensitivity of hepatocellular carcinoma (HCC) cell lines and xenograft model in response to 5-fluorouracil (5-FU) in vivo and in vitro. The treatment of the combination of 4cc with 5-FU, compared to the combination of bestain with 5-FU, markedly suppressed cell growth and induced apoptosis of HCC cells, accompanying the increase in the level of reactive oxygen species (ROS) and followed by a decrease in the mitochondrial membrane potential (ΔΨM). Furthermore, the combination of 4cc and 5-FU showed a significant inhibitory effect on the growth of HCC xenograft tumors. In addition, following the treatment of 4cc, APN activity and clonogenic formation and the number of CD13-positive cells in PLC/PRF/5 cells were significantly decreased, suggesting that 4cc may also inhibit liver cancer stem cells by CD13 inhibition. These results showed that the APN inhibitor 4cc synergizes antitumor effects of 5-FU on human liver cancer cells via ROS-mediated drug resistance inhibition and concurrent activation of the mitochondrial pathways of apoptosis.
氨肽酶N（APN，也称为CD13）参与多种类型肿瘤的细胞过程，是一个潜在的抗癌治疗靶点。在此，我们报告了APN抑制剂4cc在增强肝癌（HCC）细胞系和异种移植模型对5-氟尿嘧啶（5-FU）体内外反应敏感性方面的作用。与贝斯坦与5-FU联合使用相比，4cc与5-FU联合治疗显著抑制了HCC细胞的生长并诱导其凋亡，同时伴随着活性氧（ROS）水平的升高以及随后线粒体膜电位（ΔΨM）的降低。此外，4cc与5-FU联合使用对HCC异种移植肿瘤的生长显示出显著的抑制作用。另外，在4cc处理后，PLC/PRF/5细胞中的APN活性、克隆形成能力以及CD13阳性细胞数量均显著减少，这表明4cc可能也通过抑制CD13来抑制肝癌干细胞。这些结果表明，APN抑制剂4cc通过ROS介导的耐药性抑制以及同时激活凋亡的线粒体途径，协同增强了5-FU对人肝癌细胞的抗肿瘤作用。
