Aminopeptidase N inhibitor 4cc synergizes antitumor effects of 5-fluorouracil on human liver cancer cells through ROS-dependent CD13 inhibition

Abstract Aminopeptidase N (APN, also known as CD13) is involved in cellular processes of various types of tumors and a potential anti-cancer therapeutic target. Here, we report the effect of an APN inhibitor 4cc in enhancing sensitivity of hepatocellular carcinoma (HCC) cell lines and xenograft mode...

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Bibliographic Details
Published in:Biomedicine & pharmacotherapy 2015-12, Vol.76, p.65-72
Main Authors: Sun, Zhi-Peng, Zhang, Jian, Shi, Li-Hong, Zhang, Xiu-Rong, Duan, Yu, Xu, Wen-Fang, Dai, Gong, Wang, Xue-Jian
Format: Article
Language:English
Subjects:
4cc
5-FU
Animals
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis - drug effects
Apotosis
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - pathology
CD13
CD13 Antigens - antagonists & inhibitors
Cell Line, Tumor
Drug combination
Drug Synergism
Female
Fluorouracil - administration & dosage
Humans
Hydroxamic Acids - administration & dosage
Internal Medicine
Leucine - administration & dosage
Leucine - analogs & derivatives
Liver cancer
Liver Neoplasms - drug therapy
Liver Neoplasms - pathology
Medical Education
Membrane Potential, Mitochondrial - drug effects
Mice
Mitochondria - metabolism
Reactive Oxygen Species - metabolism
ROS
Urea - administration & dosage
Urea - analogs & derivatives
Xenograft Model Antitumor Assays
ΔΨM
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Summary:Abstract Aminopeptidase N (APN, also known as CD13) is involved in cellular processes of various types of tumors and a potential anti-cancer therapeutic target. Here, we report the effect of an APN inhibitor 4cc in enhancing sensitivity of hepatocellular carcinoma (HCC) cell lines and xenograft model in response to 5-fluorouracil (5-FU) in vivo and in vitro . The treatment of the combination of 4cc with 5-FU, compared to the combination of bestain with 5-FU, markedly suppressed cell growth and induced apoptosis of HCC cells, accompanying the increase in the level of reactive oxygen species (ROS) and followed by a decrease in the mitochondrial membrane potential (ΔΨM). Furthermore, the combination of 4cc and 5-FU showed a significant inhibitory effect on the growth of HCC xenograft tumors. In addition, following the treatment of 4cc, APN activity and clonogenic formation and the number of CD13-positive cells in PLC/PRF/5 cells were significantly decreased, suggesting that 4cc may also inhibit liver cancer stem cells by CD13 inhibition. These results showed that the APN inhibitor 4cc synergizes antitumor effects of 5-FU on human liver cancer cells via ROS-mediated drug resistance inhibition and concurrent activation of the mitochondrial pathways of apoptosis.
ISSN:0753-3322
1950-6007
DOI:10.1016/j.biopha.2015.10.023