Liposomal simvastatin inhibits tumor growth via targeting tumor-associated macrophages-mediated oxidative stress

Cancer Lett. 2015 Jan 28;356(2 Pt B):946-52. doi: 10.1016/j.canlet.2014.11.010. Epub 2014 Nov 11.

Abstract

Statins possess antitumor actions at doses 100- to 500-fold higher than those needed to lower cholesterol levels. Thus, the antitumor efficacy of statins could be improved greatly by using tumor-targeted delivery systems. Therefore the present work aims to investigate the antitumor activity of long-circulating liposome-encapsulated simvastatin (LCL-SIM) versus free SIM in B16.F10 murine melanoma-bearing mice. Our results showed that LCL-SIM inhibits strongly the B16.F10 melanoma growth (by 85%) whereas free SIM was ineffective. Moreover, the antitumor activity of LCL-SIM depends on the presence of functional tumor-associated macrophages (TAM) in tumor tissue and is mainly based on the reduction of the TAM-mediated oxidative stress as well as of the production of the hypoxia-inducible factor 1 α (HIF-1 α) in tumors. In conclusion, our findings suggest that the antitumor activity of LCL-SIM on B16.F10 melanoma growth is a result of the tumor-targeting property of the liposome formulation and is tightly dependent on the presence of TAM in tumor tissue.

Keywords: Cancer; Lipophilic statin; Liposomes; Oxidative stress; Tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Catalase / metabolism
  • Cell Proliferation / drug effects
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Liposomes*
  • Macrophages / drug effects*
  • Macrophages / pathology
  • Male
  • Malondialdehyde / metabolism
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic / drug therapy*
  • Nitric Oxide / metabolism
  • Oxidative Stress / drug effects*
  • Simvastatin / administration & dosage*
  • Simvastatin / pharmacology
  • Tumor Cells, Cultured

Substances

  • Hif1a protein, mouse
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Liposomes
  • Nitric Oxide
  • Malondialdehyde
  • Simvastatin
  • Catalase