BC-02 eradicates liver cancer stem cells by upregulating the ROS-dependent DNA damage

Dou,Chunhui; Fang,Chunyan; Zhao,Yan; Fu,Xiaoyan; Zhang,Yufei; Zhu,Dongqi; Wu,Huina; Liu,Huijie; Zhang,Jian; Xu,Wenfang; Liu,Zhijun; Wang,Hongyan; Li,Daqi; Wang,Xuejian

doi:10.3892/ijo.2017.4159

BC-02 eradicates liver cancer stem cells by upregulating the ROS-dependent DNA damage

Authors:
- Chunhui Dou
- Chunyan Fang
- Yan Zhao
- Xiaoyan Fu
- Yufei Zhang
- Dongqi Zhu
- Huina Wu
- Huijie Liu
- Jian Zhang
- Wenfang Xu
- Zhijun Liu
- Hongyan Wang
- Daqi Li
- Xuejian Wang
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Affiliations: 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, School of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, P.R. China, Department of Medicinal Chemistry, School of Pharmacy, Shandong University, Jinan, Shandong 250012, P.R. China, Department of Hematology, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
Published online on: October 16, 2017 https://doi.org/10.3892/ijo.2017.4159
Pages: 1775-1784

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Abstract

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.

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