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

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.

Copper oxide nanoparticles inhibit pancreatic tumor growth primarily by targeting tumor initiating cells

“…Specifically, it has been shown that TICs generally maintain low levels of ROS, due in part, to increased activity of antioxidant enzymes or ROS scavenging molecules 28 . In addition, ROS levels were found to be higher in ovarian and liver non-TIC cultures in comparison to TIC cultures 29,30 . We assume that CuO-NPs specifically inhibit the ability of TICs to maintain low ROS levels.…”

The Cancer Stem Cell in Hepatocellular Carcinoma

“…The same authors linked TGF-β-induced EMT to CD13 upregulation, promoting CSC survival by abrogating ROS production [183]. Several experimental approaches have been designed to target CD13 in HCC, most of them showing promising efficacy, especially in combination with cytotoxic agents [184][185][186][187][188][189]. The above-mentioned ubenimex is a protease inhibitor blocking CD13 activity and has been evaluated in other diseases; i.e., squamous cell lung carcinoma, lymphedema and pulmonary hypertension.…”

CD13 Inhibition Enhances Cytotoxic Effect of Chemotherapy Agents

“…Compound BC-02 can be degraded into bestatin and 5FU ( Dou et al, 2017 ). And BC-02 could inhibit the viability of PLC/PRF/5 and Huh7 cells more effectively, compared with single treatment of bestatin, 5FU, or a combination of 5FU and bestatin ( Figures 4A,B ).…”

“…Excess of ROS induces cytotoxicity and apoptosis of cancer cells. Our previous work also indicated that BC-02 impaires the properties of liver CSCs by targeting CD13 and upregulating the intracellular ROS and ROS-induced DNA damage ( Dou et al, 2017 ). APN inhibitor 4cc also synergizes the antitumor effects of 5FU in human liver cancer cells via ROS-mediated drug resistance inhibition and concurrent activation of the mitochondrial pathways of apoptosis ( Sun et al, 2015 ).…”

“…In the current study, we aim to understand the role of CD13 in MDR and evaluate the antitumor effect of BC-02, a novel mutual prodrug (hybrid drug) of bestatin and 5FU, which can be degraded into bestatin and 5FU ( Dou et al, 2017 ), on drug-resistant tumor cells. CD13 inhibitor bestatin and neutralizing antibody can enhance the sensitivity of tumor cells to cytotoxic agents.…”