Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
School of Clinical Medicine, Weifang Medical University, Weifang, Shandong 261053, P.R. China.
Int J Oncol. 2017 Dec;51(6):1775-1784. doi: 10.3892/ijo.2017.4159. Epub 2017 Oct 16.
Cancer stem cells (CSCs) are responsible for chemoresistance, tumor recurrence and metastasis. Reportedly, aminopeptidase N (APN, also known as CD13) is a marker for semi-quiescent CSCs and a therapeutic target in human liver CSCs. In the present study, the effect of BC-02, a compound obtained by conjugating a CD13 inhibitor bestatin and fluorouracil (5-FU), was investigated toward liver CSCs. Tumor spheres formed in serum-free culture conditions have been successfully used to enrich CSCs. In this study, the sphere cells were shown to have several characteristics of CSCs, including drug resistance, high tumorigenicity, epithelial-mesenchymal transition (EMT) phenotype, lower reactive oxygen species (ROS) levels, greater colony-forming efficiency and increased proliferation capacity in vitro. Furthermore, BC-02 effectively suppressed self-renewal and malignant proliferation of CSCs compared with 5-FU, bestatin, and even the combination of 5-FU and bestatin. In addition, cell proliferation was effectively suppressed when exposed to 5-FU plus CD13-neutralizing antibody (CD13 Ab) compared with 5-FU alone. BC-02 can effectively inhibit the activity of CD13. Results demonstrated that CD13 inhibitor BC-02 impaired the properties of liver CSCs by targeting CD13 and upregulating the intracellular ROS and ROS-induced DNA damage. BC-02 might be a potential therapeutic agent for eradicating the liver CSCs and overcoming chemoresistance in liver cancer.
癌症干细胞（CSCs）是导致化疗耐药、肿瘤复发和转移的原因。据报道，氨肽酶 N（APN，也称为 CD13）是半静息 CSCs 的标志物，也是人肝 CSCs 的治疗靶点。在本研究中，研究了通过将 CD13 抑制剂巴替丁和氟尿嘧啶（5-FU）缀合而获得的化合物 BC-02 对肝 CSCs 的作用。无血清培养条件下形成的肿瘤球体已成功用于富集 CSCs。在本研究中，球细胞表现出 CSCs 的几个特征，包括耐药性、高致瘤性、上皮-间充质转化（EMT）表型、较低的活性氧（ROS）水平、体外集落形成效率更高和增殖能力增强。此外，与 5-FU、巴替丁甚至 5-FU 和巴替丁联合相比，BC-02 能有效抑制 CSCs 的自我更新和恶性增殖。此外，与单独使用 5-FU 相比，当暴露于 5-FU 加 CD13 中和抗体（CD13 Ab）时，细胞增殖被有效抑制。BC-02 能有效抑制 CD13 的活性。结果表明，CD13 抑制剂 BC-02 通过靶向 CD13 并上调细胞内 ROS 和 ROS 诱导的 DNA 损伤来损害肝 CSCs 的特性。BC-02 可能是一种潜在的治疗药物，可用于根除肝 CSCs 并克服肝癌的化疗耐药性。
