Perifosine inhibits multiple signaling pathways in glial progenitors and cooperates with temozolomide to arrest cell proliferation in gliomas in vivo

Cancer Res. 2005 Aug 15;65(16):7429-35. doi: 10.1158/0008-5472.CAN-05-1042.

Abstract

Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for treatment of major human cancers. However, the efficacy of perifosine in human gliomas has not been established. As Akt is activated in approximately 70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model in vivo. Here we show that perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G1 and G2, and causes dose-dependent growth inhibition of mouse glial progenitors in which Akt and/or Ras-Erk 1/2 pathways are activated. Furthermore, because temozolomide is a common oral alkylating agent used in the treatment of gliomas, we investigated the effect of perifosine in combination with temozolomide. We observed an enhanced effect when both were used in culture. With these results, we combined perifosine and temozolomide as treatment of platelet-derived growth factor B-driven gliomas in mice. Animal studies showed that perifosine and temozolomide combination therapy was more effective than temozolomide treatment alone (P < 0.01). These results indicate that perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be a new candidate for glioma treatment in the clinic.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • CDC2-CDC28 Kinases / antagonists & inhibitors
  • Cell Growth Processes / drug effects
  • Cell Growth Processes / physiology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 2
  • Dacarbazine / analogs & derivatives*
  • Dacarbazine / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • G1 Phase / drug effects
  • G2 Phase / drug effects
  • Glioma / drug therapy*
  • Glioma / pathology
  • Humans
  • Mice
  • Mice, Transgenic
  • Phosphorylcholine / analogs & derivatives*
  • Phosphorylcholine / pharmacology
  • Platelet-Derived Growth Factor / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases
  • Temozolomide
  • Xenograft Model Antitumor Assays

Substances

  • Platelet-Derived Growth Factor
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Phosphorylcholine
  • perifosine
  • Dacarbazine
  • Protein Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2
  • Temozolomide