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The anti-tumor
compound D-3-deoxy-phosphatidyl-myo-inositol radiosensitizes glioblastoma
cells by inhibition of the Akt survival signaling pathway
Heather L. Glanzberg, Kerri Kislin, Chad Stadheim, Aaron A. Ambrad, Ryan
R. Falsey, Baldassarre Stea, Jesse D. Martinez, D. L. Kirpatrick, Garth Powis,
Emmanuelle J. Meuillet
Arizona Cancer Center,
University of Arizona, Tucson, AZ; ProlX Pharmaceuticals, Tucson, AZ
Glioblastoma
multiforme (GBM) constitutes the most aggressive type of brain tumor.
It is uniformly fatal, with a median survival time of only 9 months, despite
current optimal treatments, which include maximal safe resection followed by
radiation therapy (RT) with or without chemotherapy.
Insights into the signal transduction pathways that operate in these tumors have
spawned new therapeutic strategies.
Akt (protein kinase B), a serine/threonine kinase that promotes cell survival
and protects cells from apoptosis is often activated in GBM due to PTEN
mutations.
Akt binds through its pleckstrin homology (PH) domain to membrane
phosphatidylinositol-3-phosphates (PtdIns-3-P), formed by PtdIns-3-kinase
allowing it to be activated by phosphorylation by the membrane associated
kinases.
We have identified D-3-deoxy-PtdIns-myo-inositols that cannot be
phosphorylated on the 3-position of the myo-inositol ring as inhibitors
of Akt in cells.
In this study, we have investigated the combining effects of the most active
compound, i.e. D-3-deoxy-PtdIns-myo-inositol ether lipid analog or DPIEL
with radiation therapy (RT) in the human glioblastoma cancer cells (U251).
Irradiated cells were pre-incubated with 5μM
or 20μM DPIEL for
2 hours and then given 5Gy that was delivered by a 10MV Siemens linear
accelerator.
Treatment of U251 cells with RT alone caused an increase in Akt phosphorylation,
and the combination treatment of U251 cells with DPIEL prior to RT led to
complete inhibition of Akt phosphorylation.
Apoptosis was also increased upon DPIEL+RT treatment.
Clonogenic assays showed radiosensitization in U251 GBM cells by a factor of
3.78 fold.
Our results demonstrate DPIEL's potential for specifically reducing U251 GBM
clonogenic cell survival.
Thus, DPIEL appears to be a member of a new class of potential anti-cancer
agents and the combination of this compound with radiation therapy may yield
maximum therapeutic benefits for patients afflicted with GBM.
Copyright
© 2003 American Association for Cancer Research. All rights reserved
Source: http://aacr03.agora.com/planner/displayabstract.asp?presentationid=6481 |
