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

Biomed Pharmacother. 2015 Dec:76:65-72. doi: 10.1016/j.biopha.2015.10.023. Epub 2015 Nov 10.

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.

Keywords: 4cc; 5-FU; Apotosis; CD13; Drug combination; Liver cancer; ROS; ΔΨM.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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