Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-Deficient PDGF-driven murine glioblastoma Journal Article

Authors: Pitter, K. L.; Galbán, C. J.; Galbán, S.; Saeed-Tehrani, O.; Li, F.; Charles, N.; Bradbury, M. S.; Becher, O. J.; Chenevert, T. L.; Rehemtulla, A.; Ross, B. D.; Holland, E. C.; Hambardzumyan, D.
Article Title: Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-Deficient PDGF-driven murine glioblastoma
Abstract: Background: Platelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR-alpha gene locus or overexpression of the PDGF ligand, resulting in the activation of downstream kinases such as phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Aberrant PDGFR signaling is observed in approximately 25-30% of human GBMs, which are frequently molecularly classified as the proneural subclass. It would be valuable to understand how PDGFR driven GBMs respond to Akt and mTOR inhibition. Methodology/Principal Findings: Using genetically engineered PTEN-intact and PTEN-deficient PDGF-driven mouse models of GBM that closely mimic the histology and genetics of the human PDGF subgroup, we investigated the effect of inhibiting Akt and mTOR alone or in combination in vitro and in vivo. We used perifosine and CCI-779 to inhibit Akt and mTOR, respectively. Here, we show in vitro data demonstrating that the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null primary glioma cell cultures is obtained when using both inhibitors in combination. We next investigated if the effects we observed in culture could be duplicated in vivo by treating mice with gliomas for 5 days. The in vivo treatments with the combination of CCI-779 and perifosine resulted in decreased Akt and mTOR signaling, which correlated to decreased proliferation and increased cell death independent of PTEN status, as monitored by immunoblot analysis, histology and MRI. Conclusions/Significance: These findings underline the importance of simultaneously targeting Akt and mTOR to achieve significant down-regulation of the PI3K pathway and support the rationale for testing the perifosine and CCI-779 combination in the human PDGF-subgroup of GBM. © 2011 Pitter et al.
Keywords: signal transduction; protein kinase b; controlled study; treatment response; cancer combination chemotherapy; monotherapy; nonhuman; nuclear magnetic resonance imaging; cell proliferation; animal cell; mouse; mammalia; animal tissue; cell death; mus; gene overexpression; enzyme inhibition; tumor volume; animal experiment; animal model; in vivo study; in vitro study; platelet derived growth factor receptor; phosphatidylinositol 3 kinase; temsirolimus; glioma cell; glioblastoma; mammalian target of rapamycin; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; tumor cell; murinae; immunoblotting; cell cycle arrest; down regulation; perifosine
Journal Title: PLoS ONE
Volume: 6
Issue: 1
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2011-01-18
Start Page: e14545
Language: English
DOI: 10.1371/journal.pone.0014545
PROVIDER: scopus
PMCID: PMC3022633
PUBMED: 21267448
Notes: --- - "Export Date: 4 March 2011" - "Art. No.: e14545" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Eric Holland
    224 Holland
  2. Nikki Charles
    12 Charles
  3. Ken L Pitter
    51 Pitter