Differential sensitivity of human glioblastoma LN18 (PTEN-positive) and A172 (PTEN-negative) cells to Taxol for apoptosis

Brain Res. 2008 Nov 6;1239:216-25. doi: 10.1016/j.brainres.2008.08.075. Epub 2008 Sep 4.

Abstract

Glioblastoma is the most malignant brain tumor in humans and an average survival of glioblastoma patients hardly exceeds 12 months. Taxol is a plant-derived anti-cancer agent, which has been used in the treatments of many solid tumors. Deletion or mutation of phosphatase and tension homolog located on chromosome ten (PTEN) occurs in more than 80% of glioblastomas. We examined the sensitivity of human glioblastoma LN18 (PTEN-positive) and A172 (PTEN-negative) cells to Taxol for induction of apoptosis. Wright staining showed morphological features of apoptosis after treatment with different doses of Taxol for 24 h. Significant amount of apoptosis occurred in LN18 cells after treatment with 25 nM Taxol, while in A172 cells only after treatment with 50 nM Taxol. Western blotting with an antibody that could specifically detect activation or phosphorylation of Akt (p-Akt) did not show any p-Akt in LN18 cells but an increase in p-Akt in A172 cells. Activation of Akt in A172 cells could be reversed by pre-treatment of the cells with the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002, indicating involvement of PI3K activity in this process. Apoptosis occurred with an increase in Bax:Bcl-2 and mitochondrial release of cytochrome c into the cytosol leading to activation of mitochondria-dependent caspase cascade. Taxol did not cause upregulation of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, in LN18 cells but substantial upregulation of VEGF in A172 cells. After treatment with Taxol, increases in p-Akt and VEGF could maintain survival and angiogenesis, respectively, in PTEN-negative glioblastoma. As a single chemotherapy, Taxol might be more efficacious in PTEN-positive glioblastoma than in PTEN-negative glioblastoma. Thus, our study showed differential sensitivity of PTEN-positive and PTEN-negative glioblastoma cells to Taxol.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cytochromes c / metabolism
  • Cytosol / metabolism
  • Dose-Response Relationship, Drug
  • Glioblastoma / drug therapy*
  • Glioblastoma / physiopathology
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • PTEN Phosphohydrolase / deficiency
  • PTEN Phosphohydrolase / metabolism*
  • Paclitaxel / administration & dosage
  • Paclitaxel / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction / drug effects
  • Vascular Endothelial Growth Factor A / metabolism
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • BAX protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • bcl-2-Associated X Protein
  • Cytochromes c
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Caspases
  • Paclitaxel