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Perifosine-induced inhibition of Akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo.

AbstractBACKGROUND:
Neuroblastoma (NB) tumors expressing high levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB or activated Akt are associated with decreased event-free or overall survival in patients with NB. In the current study, the effect of perifosine, an Akt inhibitor, on the chemosensitivity of TrkB-expressing NB cells or tumors was evaluated.
METHODS:
A tetracycline-regulated TrkB-expressing isogenic NB cell model system was tested. In this system, NB cells were treated with etoposide and/or perifosine both in vitro and in vivo. Inhibition of the target by perifosine was evaluated by Western blot analysis or kinase activity assay. Cell survival and tumor growth were investigated.
RESULTS:
In vitro BDNF treatment induced Akt phosphorylation and rescued cells from etoposide-induced cell death in cells with high TrkB expression, but not in cells with low TrkB expression. Pretreatment of high TrkB-expressing TB3 cells with perifosine blocked BDNF/TrkB-induced Akt phosphorylation and inhibited BDNF's protection of TB3 cells from etoposide treatment. In vivo, tumors with high TrkB expression were found to have elevated levels of phosphorylated Akt and were less sensitive to etoposide treatment compared with tumors with low TrkB expression. Mice treated with a combination of perifosine and etoposide were found to have a statistically significant decrease in tumor growth compared with mice treated with either etoposide or perifosine alone. Activation of Akt through the BDNF/TrkB signaling pathway induced chemoresistance in NB in vivo.
CONCLUSIONS:
Perifosine-induced inhibition of Akt increased the sensitivity of NB to chemotherapy. The results of the current study support the future clinical evaluation of an Akt inhibitor combined with cytotoxic drugs for the improvement of treatment efficacy.
AuthorsZhijie Li, Doo-Yi Oh, Katsuya Nakamura, Carol J Thiele
JournalCancer (Cancer) Vol. 117 Issue 23 Pg. 5412-22 (Dec 01 2011) ISSN: 1097-0142 [Electronic] United States
PMID21590687 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
CopyrightCopyright © 2011 American Cancer Society.
Chemical References
  • Brain-Derived Neurotrophic Factor
  • Phosphorylcholine
  • perifosine
  • Etoposide
  • Receptor, trkB
  • Proto-Oncogene Proteins c-akt
  • Tetracycline
Topics
  • Brain Neoplasms (drug therapy, pathology)
  • Brain-Derived Neurotrophic Factor (analysis, physiology)
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Etoposide (pharmacology)
  • Humans
  • Neuroblastoma (drug therapy, pathology)
  • Phosphorylation
  • Phosphorylcholine (analogs & derivatives, pharmacology)
  • Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
  • Receptor, trkB (analysis, physiology)
  • Tetracycline (pharmacology)

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