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

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.

• Authors: Marius Costel Alupei, Emilia Licarete, Laura Patras, Manuela Banciu
• Journal: Cancer letters (Cancer Lett) Vol. 356 Issue 2 Pt B Pg. 946-52 (Jan 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25444912 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Ireland Ltd.

Chemical References

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

Topics

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