HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Combination of sublethal concentrations of epidermal growth factor receptor inhibitor and microtubule stabilizer induces apoptosis of glioblastoma cells.

Abstract
The oncogenic epidermal growth factor receptor (EGFR) pathway triggers downstream phosphatidylinositol 3-kinase (PI3K)/RAS-mediated signaling cascades. In transgenic mice, glioblastoma cannot develop on single but only on simultaneous activation of the EGFR signaling mediators RAS and AKT. However, complete blockade of EGFR activation does not result in apoptosis in human glioblastoma cells, suggesting additional cross-talk between downstream pathways. Based on these observations, we investigated combination therapies using protein kinase inhibitors against EGFR, platelet-derived growth factor receptor, and mammalian target of rapamycin, assessing glioblastoma cell survival. Clinically relevant doses of AEE788, Gleevec (imatinib), and RAD001 (everolimus), alone or in combinations, did not induce glioblastoma cell apoptosis. In contrast, simultaneous inactivation of the EGFR downstream targets mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase and PI3K by U0126 and wortmannin triggered rapid tumor cell death. Blocking EGFR with AEE788 in combination with sublethal concentrations of the microtubule stabilizer patupilone also induced apoptosis and reduced cell proliferation in glioblastoma cells, accompanied by reduced AKT and ERK activity. These data underline the critical role of the PI3K/AKT and the RAS/RAF/mitogen-activated protein/ERK kinase/ERK signaling cascades in the cell-intrinsic survival program of sensitive glioblastoma cell lines. We conclude that drug combinations, which down-regulate both ERK and protein kinase B/AKT activity, may prove effective in overcoming cell resistance in a subgroup of glioblastoma.
AuthorsMike Failly, Serdar Korur, Viviane Egler, Jean-Louis Boulay, Maria Maddalena Lino, Roland Imber, Adrian Merlo
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 2 Pg. 773-81 (Feb 2007) ISSN: 1535-7163 [Print] United States
PMID17308073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzamides
  • Epothilones
  • Immunosuppressive Agents
  • Phorbol Esters
  • Piperazines
  • Protein Kinase Inhibitors
  • Purines
  • Pyrimidines
  • Imatinib Mesylate
  • Everolimus
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase 1
  • AEE 788
  • epothilone B
  • Sirolimus
Topics
  • Apoptosis (drug effects)
  • Benzamides
  • Blotting, Western
  • Cell Cycle (drug effects)
  • Cell Proliferation (drug effects)
  • Cell Survival (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Epothilones (pharmacology)
  • ErbB Receptors (antagonists & inhibitors, metabolism)
  • Everolimus
  • Glioblastoma (drug therapy, metabolism)
  • Humans
  • Imatinib Mesylate
  • Immunosuppressive Agents (pharmacology)
  • MAP Kinase Kinase 1 (metabolism)
  • Microtubules (drug effects, metabolism)
  • Mitogen-Activated Protein Kinase 1 (metabolism)
  • Mitogen-Activated Protein Kinase 3 (metabolism)
  • Phorbol Esters (pharmacology)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Piperazines (pharmacology)
  • Protein Kinase Inhibitors (pharmacology)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Purines (pharmacology)
  • Pyrimidines (pharmacology)
  • Signal Transduction (drug effects)
  • Sirolimus (analogs & derivatives, pharmacology)
  • Tumor Cells, Cultured (drug effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: