Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model

PLoS One. 2013;8(1):e53992. doi: 10.1371/journal.pone.0053992. Epub 2013 Jan 9.

Abstract

Chronic liver disease may result in a sequential progression through fibrosis, cirrhosis and lead, eventually, to hepatocellular carcinoma (HCC). Hepatic stellate cells (HSC) seem to be responsible for the fibrogenic response through the activation of an autocrine loop involving the chemokine receptor, CCR5. However, the role of CCR5 in HCC remains poorly understood. Since this receptor is also one of the main ports of entry for the human immunodeficiency virus (HIV), several CCR5 inhibitors are being used in the clinic to reduce viral load. We used one of these inhibitors, maraviroc (MVC), in a mouse model of diet-induced HCC to investigate whether this intervention would reduce disease progression. Animals treated with MVC on top of a normal control diet did not present any evidence of toxicity or any morphological change when compared with non-treated mice. Animals treated with MVC presented higher survival, less liver fibrosis, lower levels of liver injury markers and chemokines, less apoptosis, lower proliferation index, and lower tumor burden than their counterparts receiving only the hepatotoxic diet. In addition, MVC inhibits HSC activation markers such as phosphorylation of p38 and ERK, and increases hepatocyte survival. This study suggests that MVC, a well tolerated and clinically characterized drug, may be used as a preventative treatment for HCC. Clinical studies are needed to demonstrate the efficacy of this drug, or other CCR5 inhibitors, in patients with high risk of developing HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • CCR5 Receptor Antagonists
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Proliferation / drug effects
  • Cyclohexanes / administration & dosage*
  • Humans
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • MAP Kinase Signaling System / drug effects
  • Maraviroc
  • Mice
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Phosphorylation
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism*
  • Triazoles / administration & dosage*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • CCR5 Receptor Antagonists
  • Cyclohexanes
  • Receptors, CCR5
  • Triazoles
  • p38 Mitogen-Activated Protein Kinases
  • Maraviroc

Grant support

This study was supported by a grant from Fundación Rioja Salud (FRS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.