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 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.

• Authors: Zhi-Peng Sun, Jian Zhang, Li-Hong Shi, Xiu-Rong Zhang, Yu Duan, Wen-Fang Xu, Gong Dai, Xue-Jian Wang
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 76 Pg. 65-72 (Dec 2015) ISSN: 1950-6007 [Electronic] France
• PMID: 26653552 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Chemical References

• 4-methyl-2-(3-(naphthalen-1-yl-methyl)ureido)pentanoic acid hydroxyamide
• Hydroxamic Acids
• Reactive Oxygen Species
• Urea
• CD13 Antigens
• Leucine
• Fluorouracil

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• CD13 Antigens (antagonists & inhibitors)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Line, Tumor
• Drug Synergism
• Female
• Fluorouracil (administration & dosage)
• Humans
• Hydroxamic Acids (administration & dosage)
• Leucine (administration & dosage, analogs & derivatives)
• Liver Neoplasms (drug therapy, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mitochondria (metabolism)
• Reactive Oxygen Species (metabolism)
• Urea (administration & dosage, analogs & derivatives)
• Xenograft Model Antitumor Assays