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In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine.

AbstractBACKGROUND:
Activated AKT is a marker of decreased event-free or overall survival in neuroblastoma (NB) patients. The aim of this study was to investigate the effect of perifosine, a nontoxic AKT inhibitor, as a single agent on NB cell growth in vitro and in vivo.
METHODS:
Four human NB cell lines (AS, NGP, BE2, and KCNR) were treated with increasing concentrations of perifosine, and a quantitative analysis of cell death (apoptosis) was performed by using MTS and caspase-3/7 activity assays. Survival of mice carrying xenograft NB tumors that were treated with perifosine (n = 6-7 mice per group) was compared with that of untreated mice (n = 7 mice per group) using Kaplan-Meier analysis. Tumor volumes were calculated to determine the effect of perifosine on NB tumor growth. Phosphorylation of AKT and expression of cleaved caspase-3 were measured in proteins from the tumors. All statistical tests were two-sided.
RESULTS:
Perifosine, at 30 muM concentration, decreased AKT phosphorylation and increased apoptosis in all four NB cell lines in vitro. Perifosine-treated mice bearing xenograft NB tumors had longer survival than untreated mice (untreated vs treated, median survival: AS, 13 days, 95% confidence interval [CI] = 11 to 16 days vs not reached, P = .003; NGP, 22 days, 95% CI = 20 to 26 days vs not reached, P = .013; BE2, 24 days, 95% CI = 21 to 27 days vs not reached, P < .001; and KCNR, 18 days, 95% CI = 18 to 21 days vs not reached, P < .001). Perifosine treatment induced regression in AS tumors, growth inhibition in BE2 tumors, and slower growth in NGP and KCNR tumors. Inhibition of AKT phosphorylation and induction of caspase-dependent apoptosis were noted in tumors of perifosine-treated mice in all four in vivo NB tumor models.
CONCLUSIONS:
Perifosine inhibited the activation of AKT and was an effective cytotoxic agent in NB cells in vitro and in vivo. Our study supports the future clinical evaluation of perifosine for the treatment of NB tumors.
AuthorsZhijie Li, Fei Tan, David J Liewehr, Seth M Steinberg, Carol J Thiele
JournalJournal of the National Cancer Institute (J Natl Cancer Inst) Vol. 102 Issue 11 Pg. 758-70 (Jun 02 2010) ISSN: 1460-2105 [Electronic] United States
PMID20463309 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
Chemical References
  • Antineoplastic Agents
  • Growth Inhibitors
  • Luminescent Agents
  • Phosphorylcholine
  • perifosine
  • Luciferases
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
  • Caspase 7
Topics
  • Analysis of Variance
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Caspase 3 (metabolism)
  • Caspase 7 (metabolism)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Clinical Trials as Topic
  • Disease Models, Animal
  • Growth Inhibitors (pharmacology, therapeutic use)
  • Humans
  • In Vitro Techniques
  • Kaplan-Meier Estimate
  • Luciferases
  • Luminescent Agents
  • Mice
  • Mutation
  • NIH 3T3 Cells
  • Neuroblastoma (drug therapy, genetics, metabolism)
  • Phosphorylation (drug effects)
  • Phosphorylcholine (analogs & derivatives, pharmacology, therapeutic use)
  • Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
  • Transplantation, Heterologous

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