Gambogenic acid-induced time- and dose-dependent growth inhibition and apoptosis involving Akt pathway inactivation in U251 glioblastoma cells

J Nat Med. 2012 Jan;66(1):62-9. doi: 10.1007/s11418-011-0553-7. Epub 2011 Aug 31.

Abstract

Glioblastoma multiforme is the most common and aggressive type of primary brain tumor. Uncontrolled activation of the PI3K/Akt signaling pathway resulting from genetic alterations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and epidermal growth factor receptor (EGFR) correlates with poor prognosis and resistance to chemotherapy and radiotherapy of glioblastomas. In this study, we found that gambogenic acid (GNA), a polyprenylated xanthone isolated from the traditional medicine gamboge, efficiently arrested the cell cycle at the G(0)/G(1) phase by specifically repressing the expression of cyclin D1 and cyclin E, suppressed cell proliferation, colony formation and cell migration, and induced caspase-dependent apoptosis in U251 glioblastoma cells in a time- and dose-dependent manner. The pro-apoptotic effect of GNA on U251 cells was shown to be mediated through inactivation of the Akt pathway, because GNA efficiently suppressed the expression level of EGFR and reduced the phosphorylation of Akt (T308) and GSK3β (S9). Furthermore, the combined treatment with LY294002, a specific inhibitor of the PI3K/Akt kinase pathway, and GNA showed a synergistic or additive effect on the growth of U251 cells. Our results showed that GNA is a promising therapeutic agent for glioblastomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / isolation & purification
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / pathology
  • Caspases / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • ErbB Receptors / metabolism
  • Garcinia* / chemistry
  • Glioblastoma / enzymology*
  • Glioblastoma / pathology
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction / drug effects*
  • Terpenes / isolation & purification
  • Terpenes / pharmacology*
  • Time Factors
  • Xanthenes
  • Xanthones / isolation & purification
  • Xanthones / pharmacology*

Substances

  • Antineoplastic Agents, Phytogenic
  • Protein Kinase Inhibitors
  • Terpenes
  • Xanthenes
  • Xanthones
  • neo-gambogic acid
  • Phosphatidylinositol 3-Kinase
  • EGFR protein, human
  • ErbB Receptors
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Caspases