CD13 Inhibition Enhances Cytotoxic Effect of Chemotherapy Agents

Abstract

Multidrug resistance (MDR) of hepatocellular carcinoma is a serious problem. Although CD13 is a biomarker in human liver cancer stem cells, the relationship between CD13 and MDR remains uncertain. This study uses liver cancer cell model to understand the role of CD13 in enhancing the cytotoxic effect of chemotherapy agents. Cytotoxic agents can induce CD13 expression. CD13 inhibitor, bestatin, enhances the antitumor effect of cytotoxic agents. Meanwhile, CD13-targeting siRNA and neutralizing antibody can enhance the cytotoxic effect of 5-fluorouracil (5FU). CD13 overexpression increases cell survival upon cytotoxic agents treatment, while the knockdown of CD13 causes hypersensitivity of cells to cytotoxic agents treatment. Mechanistically, the inhibition of CD13 leads to the increase of cellular reactive oxygen species (ROS). BC-02 is a novel mutual prodrug (hybrid drug) of bestatin and 5FU. Notably, BC-02 can inhibit cellular activity in both parental and drug-resistant cells, accompanied with significantly increased ROS level. Moreover, the survival time of Kunming mice bearing H22 cells under BC-02 treatment is comparable to the capecitabine treatment at maximum dosage. These data implicate a therapeutic method to reverse MDR by targeting CD13, and indicate that BC-02 is a potent antitumor compound.

Suppression of CD13 Enhances the Cytotoxic Effect of Chemotherapeutic Drugs in Hepatocellular Carcinoma Cells

“…All cell lines were cultured at 37°C in a humidified atmosphere of 5% CO 2 . We constructed stable CD13 overexpression (PLC/PRF/5/CD13) and knockdown (PLC/PRF/5/CD13 short hairpin RNA) PLC/PRF/5 cells by using the lentiviral vector (Genechem, China) and puromycin screening ( Zhang et al, 2018 ).…”

“…For this reason, therapy used to eliminate or elevate ROS production may be potentially effective, although it is a rather challenging concept. We have previously reported that CD13 inhibitor, neutralizing antibody, and CD13-targeted siRNA could up-regulate intracellular ROS level and enhance the anti-tumor effect of chemotherapy agents ( Zhang et al, 2018 ).…”

CD13 Induces Autophagy to Promote Hepatocellular Carcinoma Cell Chemoresistance Through the P38/Hsp27/CREB/ATG7 Pathway

“…The human hepatoma cell lines PLC/PRF/5 and Huh7 were obtained from the Cell Bank of Shanghai (Shanghai, China). We constructed stable CD13 overexpression (PLC/PRF/5/ CD13) and knockdown (PLC/PRF/5/CD13 short hairpin RNA) PLC/ PRF/5 cells by using the lentiviral vector (Genechem, China) and puromycin screening (Zhang et al, 2018). The obtained PLC/PRF/5 and Huh7 cell lines were respectively maintained in modified Eagle's medium and Dulbecco's modified Eagle's medium supplemented with 10% FBS and penicillin-streptomycin in a humidified incubator under of 5% CO 2 at 37°C.…”

“…We previously reported that ubenimex and a neutralizing antibody could enhance the antitumor effects of 5FU and other cytotoxic agents on HCC cell lines by upregulating the level of intracellular reactive oxygen species (ROS). Whereas CD13 overexpression could strengthen the resistance of PLC/PRF/5 cells to chemotherapeutic drugs, knockdown of CD13 remarkably increases the sensitivity of PLC/ PRF/5 cells to antitumor drugs (Zhang et al, 2018).…”

Redox regulation of cell state and fate

“…In HCC, chemotherapeutic drugs or radiation treatment invariably result in the enrichment of CSCs with a ROS low profile that is accompanied with either the ability to reduce ROS-induced DNA damage after genotoxic insult, increased GSH levels or MAPK/PI3K activation [56], [57], [58]. Importantly, the inhibition of CD13 (a liver CSC marker) or treatment of CD133 + CSCs with sulfasalazine (a potent xCT inhibitor) overcomes resistance to chemotherapeutic and radiation treatment by increasing ROS levels in the resistant cells [56], [58], [59]. In pancreatic adenocarcinoma, ROS low CSC are also implicated in radioresistance [60], [61].…”