Related Experiment Video
Updated: Jun 5, 2026
Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells
Published on: August 21, 2013
Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient
Kenneth L Pitter1, Craig J Galbán, Stefanie Galbán
1Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
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.
Insights
Simultaneously inhibiting Akt and mTOR with perifosine and CCI-779 effectively reduces proliferation and increases cell death in Platelet-Derived Growth Factor Receptor (PDGFR) driven glioblastoma models, regardless of PTEN status.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Deregulation of Platelet-Derived Growth Factor Receptor (PDGFR) signaling, particularly PDGFR-alpha, is implicated in approximately 25-30% of human Glioblastoma Multiforme (GBM).
- This aberrant signaling activates key downstream kinases like phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), driving tumor growth.
- Understanding the response of PDGFR-driven GBMs to Akt and mTOR inhibition is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the efficacy of inhibiting Akt and mTOR, alone and in combination, in PDGFR-driven GBM mouse models.
- To evaluate the impact of these inhibitors on GBM cell proliferation and survival.
- To determine if the combination therapy's effectiveness is dependent on PTEN status.
Main Methods:
- Utilized genetically engineered PTEN-intact and PTEN-deficient PDGF-driven mouse models of GBM.
- Employed perifosine to inhibit Akt and CCI-779 to inhibit mTOR.
- Conducted in vitro studies on primary glioma cell cultures and in vivo studies involving 5-day treatment of tumor-bearing mice.
- Assessed signaling pathway activity, proliferation, and cell death using immunoblot analysis, histology, and MRI.
Main Results:
- In vitro studies demonstrated that combining perifosine and CCI-779 achieved the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null glioma cells.
- In vivo treatment with the combination therapy led to decreased Akt and mTOR signaling.
- This reduction in signaling correlated with decreased tumor cell proliferation and increased cell death, independent of PTEN status.
Conclusions:
- Simultaneous inhibition of Akt and mTOR is essential for significant downregulation of the PI3K pathway in PDGFR-driven GBM.
- The combination of perifosine and CCI-779 shows promise for treating the PDGF-subgroup of GBM.
- These findings support the clinical investigation of this combination therapy in human GBM patients.
