BC-02 eradicates liver cancer stem cells by upregulating the ROS-dependent DNA damage
BC-02 eradicates liver cancer stem cells by upregulating the ROS-dependent DNA damage
复制标题
BC-02 通过上调 ROS 依赖性 DNA 损伤来根除肝癌干细胞。
DOI：
10.3892/ijo.2017.4159
复制
发表时间：
2017-12-01
影响因子：
5.2
通讯作者：
Wang, Xuejian
中科院分区：
文献类型：
--
作者：
Dou, Chunhui;Fang, Chunyan;Wang, Xuejian
肿瘤干细胞（Cancer stem cells, CSCs）与化疗耐药、肿瘤复发和转移有关。据报道，氨基肽酶N （APN，也称为CD13）是半静止CSCs的标记物，也是人肝CSCs的治疗靶点。在本研究中，BC-02是一种由CD13抑制剂贝司他汀和氟尿嘧啶（5-FU）偶联得到的化合物，研究了BC-02对肝CSCs的影响。在无血清培养条件下形成的肿瘤球已成功用于培养CSCs。在这项研究中，球形细胞被证明具有CSCs的几个特征，包括耐药、高致瘤性、上皮-间充质转化（EMT）表型、较低的活性氧（ROS）水平、更高的集落形成效率和体外增殖能力。BC-02与5-FU、bestatin，甚至与5-FU和bestatin联用相比，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，5-FU加CD13中和抗体（CD13 Ab）可有效抑制细胞增殖。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，上调细胞内ROS和ROS诱导的DNA损伤，从而损害肝CSCs的特性。BC-02可能是一种潜在的治疗肝癌CSCs和克服化疗耐药的药物。
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.