title: 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.affiliation: Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania; Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania.
authors.forename: Marius Costel
authors.initials: MC
authors.lastname: Alupei
authors.affiliation: Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania.
authors.forename: Emilia
authors.initials: E
authors.lastname: Licarete
authors.affiliation: Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania; Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania.
authors.forename: Laura
authors.initials: L
authors.lastname: Patras
authors.affiliation: Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania; Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania. Electronic address: manuela.banciu@ubbcluj.ro.
authors.forename: Manuela
authors.initials: M
authors.lastname: Banciu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002374:Catalase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D019821:Simvastatin / Q000008:administration & dosage* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C497443:Hif1a protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008081:Liposomes; D009569:Nitric Oxide; D008315:Malondialdehyde; D019821:Simvastatin; D002374:Catalase
keywords: Cancer; Lipophilic statin; Liposomes; Oxidative stress; Tumor-associated macrophages