Induction of the fibrinolytic system by cartilage extract mediates its antiangiogenic effect in mouse glioma

Microvasc Res. 2011 Jul;82(1):6-17. doi: 10.1016/j.mvr.2011.03.002. Epub 2011 Mar 13.

Abstract

Both the antiangiogenic and antitumoral activity of shark cartilage extracts (SCE) have been demonstrated in animal models and clinical trials. Studies reported that SCE induces the expression of tissue plasminogen activator gene (PLAT) in endothelial cells and increases the activity of the protein (t-PA) in vitro. The aim of this study was to demonstrate the crucial role of t-PA induction in the antiangiogenic and antitumor activity of SCE in experimental glioma. This study showed antiangiogenic and antitumoral effects of SCE in three mice glioma models (C6, HGD and GL26). Histological examination suggested perivascular proteolysis and edema as well as important intratumoral necrosis, which artefactually increased the tumor volume at high doses. Thus, the antiangiogenic effect of SCE correlated with the presence of t-PA and angiostatin in degenerating vessels. Functional in vivo experiments were conducted to modulate the plasminogen pathway. No antiangiogenic effect was observed on tumors overexpressing the plasminogen activator inhibitor-1 (PAI-1). Moreover, therapeutical effects were neutralized in mice that were cotreated with ε-aminocaproic acid (EACA, 120 mg/kg p.o.), an inhibitor that blocks the high-affinity lysine binding sites of both plasminogen and plasmin. In contrast, cotreatment with N-acetylcysteine (NAC, 7,5mg/kg i.p.), a sulfhydril donor that reduces plasmin into angiostatin or other antiangiogenic fragments, increased the benefit of SCE on mice survival. In subcutaneous models, NAC prevented the increase in tumor volume caused by high doses of cartilage extract. In conclusion, this study indicates that induction of t-PA by shark cartilage extract plays an essential role in its antiangiogenic activity, but that control of excessive proteolysis by a plasmin reductor could prevent edema and uncover the full benefit of shark cartilage extract in the treatment of intracranial tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / metabolism
  • Acetylcysteine / pharmacology
  • Aminocaproic Acid / pharmacology
  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use
  • Angiostatins / metabolism
  • Animals
  • Blood Vessels / metabolism
  • Blood Vessels / pathology
  • Caudate Nucleus / pathology
  • Cell Line, Tumor
  • Fibrinolysin / antagonists & inhibitors
  • Fibrinolysin / pharmacology
  • Fibrinolysis / drug effects*
  • Glioma / blood supply
  • Glioma / drug therapy*
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology
  • Plasminogen / antagonists & inhibitors
  • Plasminogen / metabolism
  • Plasminogen Activator Inhibitor 1 / genetics
  • Plasminogen Activator Inhibitor 1 / pharmacology
  • Rats
  • Survival Analysis
  • Tissue Extracts / administration & dosage
  • Tissue Extracts / pharmacology*
  • Tissue Extracts / therapeutic use*
  • Tissue Plasminogen Activator / antagonists & inhibitors
  • Tissue Plasminogen Activator / metabolism
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Plasminogen Activator Inhibitor 1
  • Tissue Extracts
  • shark cartilage extract
  • Angiostatins
  • Plasminogen
  • Tissue Plasminogen Activator
  • Fibrinolysin
  • Aminocaproic Acid
  • Acetylcysteine