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Enhanced antitumor effect of YM872 and AG1296 combination treatment on human glioblastoma xenograft models.

AbstractOBJECT:
Blockade of Ca(++)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) inhibits the proliferation of human glioblastoma by inhibiting Akt phosphorylation, which is independent of the phosphatidylinositol 3-kinase pathway. Inhibiting platelet-derived growth factor receptor (PDGFR)-mediated phosphorylation causes growth inhibition in glioblastoma cells. The authors of this study investigated the effects of YM872 and AG1296, singly and in combination and targeting different pathways upstream of Akt, on Akt-mediated tumor growth in glioblastoma cells in vivo and in vitro.
METHODS:
The expression of AMPAR, PDGFR, and c-kit in glioblastoma cells was analyzed via immunofluorescence. Glioblastoma cells, both in culture and in xenografts grown in mice, were treated with YM872 and AG1296, singly or in combination. Inhibition of tumor growth was observed after treatment in the xenograft model. Cell proliferation assays were performed using anti-Ki 67 antibody in vivo and in vitro. The CD34-positive tumor vessel counts within the vascular hot spots of tumor specimens were evaluated. Phosphorylation of Akt was studied using Western blot analysis.
RESULTS:
Combined administration of YM872 and AG1296 had a significant enhanced effect on the inhibition of cell proliferation and reduction of tumor vascularity in the xenograft model. These agents singly and in combination demonstrated a significant reduction of Akt phosphorylation at Ser473 and inhibition of tumor proliferation in vitro, although combined administration had no enhanced antitumor effects.
CONCLUSIONS:
The strongly enhanced antitumor effect of this combination therapy in vivo rather than in vitro may be attributable to disruption of the aberrant vascular niche. This combination therapy might provide substantial benefits to patients with glioblastoma.
AuthorsTakashi Watanabe, Toshiyuki Ohtani, Masanori Aihara, Shogo Ishiuchi
JournalJournal of neurosurgery (J Neurosurg) Vol. 118 Issue 4 Pg. 838-45 (Apr 2013) ISSN: 1933-0693 [Electronic] United States
PMID23311938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Imidazoles
  • Quinoxalines
  • Receptors, AMPA
  • Tyrphostins
  • YM 872
  • 6,7-dimethoxy-3-phenylquinoxaline
  • Proto-Oncogene Proteins c-kit
  • Receptors, Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-akt
Topics
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Brain Neoplasms (drug therapy, metabolism, pathology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Glioblastoma (drug therapy, metabolism, pathology)
  • Humans
  • Imidazoles (pharmacology, therapeutic use)
  • In Vitro Techniques
  • Mice
  • Mice, Nude
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Proto-Oncogene Proteins c-kit (metabolism)
  • Quinoxalines (pharmacology, therapeutic use)
  • Receptors, AMPA (antagonists & inhibitors)
  • Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors, metabolism)
  • Transplantation, Heterologous
  • Treatment Outcome
  • Tyrphostins (pharmacology, therapeutic use)

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