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

Area of Science:

• Oncology
• Cancer Stem Cell Biology
• Drug Discovery

Background:

• Cancer stem cells (CSCs) drive chemoresistance, recurrence, and metastasis in liver cancer.
• Aminopeptidase N (APN, CD13) is identified as a marker and therapeutic target for liver CSCs.

Purpose of the Study:

• To investigate the efficacy of BC-02, a conjugate of a CD13 inhibitor (bestatin) and 5-fluorouracil (5-FU), against liver CSCs.
• To evaluate BC-02's potential in overcoming chemoresistance and eradicating liver CSCs.

Main Methods:

• Enrichment of liver CSCs using tumor sphere formation in serum-free conditions.
• Assessment of CSC characteristics: drug resistance, tumorigenicity, EMT, ROS levels, colony formation, and proliferation.
• Evaluation of BC-02's effect on CSC self-renewal and proliferation compared to 5-FU, bestatin, and their combination.
• Investigation of BC-02's mechanism involving CD13 inhibition, ROS upregulation, and DNA damage.

Main Results:

• BC-02 significantly suppressed liver CSC self-renewal and proliferation more effectively than 5-FU, bestatin, or their combination.
• BC-02 demonstrated superior inhibition of proliferation compared to 5-FU plus a CD13-neutralizing antibody.
• BC-02 effectively inhibited CD13 activity, leading to impaired CSC properties via ROS upregulation and DNA damage.

Conclusions:

• BC-02 is a potent inhibitor of liver CSCs, targeting CD13 to disrupt their essential properties.
• BC-02 represents a potential therapeutic strategy for eradicating liver CSCs and overcoming chemoresistance in liver cancer.