Enhanced expression of proapoptotic and autophagic proteins involved in the cell death of glioblastoma induced by synthetic glycans

J Neurosurg. 2014 Jun;120(6):1298-308. doi: 10.3171/2014.1.JNS131534. Epub 2014 Mar 28.

Abstract

Object: Glioblastoma is the most aggressive malignant brain tumor, and overall patient survival has not been prolonged even by conventional therapies. Previously, the authors found that chemically synthesized glycans could be anticancer agents against growth of a series of cancer cells. In this study, the authors examined the effects of glycans on the growth of glioblastoma cells both in vitro and in vivo.

Methods: The authors investigated not only the occurrence of changes in the cell signaling molecules and expression levels of various proteins related to cell death, but also a mouse model involving the injection of glioblastoma cells following the administration of synthetic glycans.

Results: Synthetic glycans inhibited the growth of glioblastoma cells, induced the apoptosis of the cells with cleaved poly (adenosine diphosphate-ribose) polymerase (PARP) expression and DNA fragmentation, and also caused autophagy, as shown by the detection of autophagosome proteins and monodansylcadaverine staining. Furthermore, tumor growth in the in vivo mouse model was significantly inhibited. A dramatic induction of programmed cell death was found in glioblastoma cells after treatment with synthetic glycans.

Conclusions: These results suggest that synthetic glycans could be a promising novel anticancer agent for performing chemotherapy against glioblastoma.

Keywords: AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Akt = protein kinase B; CPI = cell proliferation inhibition; GChol = GlcNAcβChol; GGChol = GlcNAcβ1,3 GalβChol; GalβChol = d-galactose β cholestanol; GlcNAcβ1,3 = N-acetyl-d-glucosamine β1,3; GluR1 = glutamate receptor 1; GluR4 = glutamate receptor 4; HO342 = Hoechst 33342; HP-β-CD = hydroxypropyl-β-cyclodextrin; MDC = monodansylcadaverine; PARP = poly (adenosine diphosphate-ribose) polymerase; PI3K = phosphatidylinositol 3-kinase; Z-VAD-FMK = benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone; apoptosis; autophagy; glioblastoma; mTOR = mammalian target of rapamycin; oncology; synthetic glycan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy / drug effects*
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cholestanols / pharmacology
  • Cholestanols / therapeutic use
  • DNA Fragmentation / drug effects
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / drug therapy
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology*
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Nude
  • Poly(ADP-ribose) Polymerases / metabolism
  • Polysaccharides / pharmacology*
  • Polysaccharides / therapeutic use
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Cholestanols
  • Polysaccharides
  • Poly(ADP-ribose) Polymerases