Abstract
BackgroundDung beetle glycosaminoglycan is known to possess anti-aging activities. However, its anti-cancer mechanisms are not fully elucidated yet. The objective of this study was to evaluate the anti-cancer effect of insect-derived polymer dung beetle glycosaminoglycan (GAG) after intraperitoneally injecting it to melanoma mice induced by B16F10 cells.MethodsTo determine molecular mechanism involved in the anti-cancer effect of dung beetle GAG, its origin N-glycan under 3KD Dalton was assayed for melanoma cell cytotoxicity. Quantitative comparisons of adhesive molecule on extracellular matrix and activities of tissue inhibitor of metalloprotease 2 (TIMP-2) were also investigated. In vivo anti-cancer effect of dung beetle GAG on solid tumor size, survival time and gene-expression profiles was also assayed using B10F10 melanoma mice model. Mice with induced melanoma were then treated with Catharsius molossus (dung beetle) GAG (CaG) at 5 mg/kg for 8 weeks to investigate its anti-cancer effects compared to bumblebee (Bombus ignitus) queen glycosaminoglycan (IQG) and Huechys sanguinea glycosaminoglycan (HEG).ResultsThese N-glycans derived from these GAG were composed of many linear heparinoid polysaccharides, polymers with hexose and N-acetylhexose. Adminstration with these GAGs increased survival time and decreased melanoma sizes in mice, in accordance with their inhibitory effects on cell growth ratio of melanoma B16F10. In addition, treatment with N-glycans derived from theses glycosaminoglycan increased activities of TIMP-2 in HMVEC cells pretreated with TNF-alpha and in melanoma cells, suggesting that they had anti-inflammatory and anticancer activities. In DNA microarray results, compared to control, CaG treated mouse group showed upregulation of 192 genes including collagen,typeI,alpha1 (Col1a1), consistent with the highly increased in vitro extracellular matrix (ECM) adhesion on collagen 1 and up-regulation of heparanase (Hpse). After treatment with CaG, a total of 152 genes were down-regulated, including nuclear RNA export factor (Nxf3) and hyaluronan proteoglycan link protein1 (Hapln1).ConclusionsGlycosaminoglycan, CaG can strengthen ECM by increasing activity of TIMP-2 and adhesion activity on collagen known to inhibit changes of ECM, leading to tumor cell invasion and progression.
Highlights
Dung beetle glycosaminoglycan is known to possess anti-aging activities
Anticancer activities of insect extract containing GAG are associated with modulation of the production of various cytokines, nitric oxide related to regulation of inflammation, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM) related to defense and repair, and matrix metalloproteinases (MMP) in vitro [3]
Anti-cancer activity of N-glycan derived from Catharsius molossus (dung beetle) GAG (CaG), Bumblebee queen glycosaminoglycan (IQG) or Huechys sanguinea glycosaminoglycan (HEG) in melanoma cells To determine the anticancer activity of purified N-glycan derived from insect GAG, cytotoxicity against B16F10 melanoma cells was determined, using Cell Proliferation Kit (XTT, sodium 3′-[1-(phenylamino-carbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro) benzene sulfonic acid hydrate) (Roche Diagnostics GmbH, Mannheim, Germany) according to the kit manual
Summary
Dung beetle glycosaminoglycan is known to possess anti-aging activities. its anti-cancer mechanisms are not fully elucidated yet. The objective of this study was to evaluate the anti-cancer effect of insectderived polymer dung beetle glycosaminoglycan (GAG) after intraperitoneally injecting it to melanoma mice induced by B16F10 cells. Glycosaminoglycans (GAGs) are linear mucopolysaccharides with repeating disaccharide units. They are minor components of native tissues, they play key roles in regulation of various physiological processes [1]. Anticancer activities of insect extract containing GAG are associated with modulation of the production of various cytokines (vascular endothelial growth factor, prostaglandin E2, secretary phospholipase A2), nitric oxide related to regulation of inflammation, vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM) related to defense and repair, and matrix metalloproteinases (MMP) in vitro [3]. Anti-cancer effects of versatile insect GAGs or N-glycans (purified from theses GAGs) on melanoma using animal models are insufficient
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