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Research Articles: Targets

Inhibition of Akt by the alkylphospholipid perifosine does not enhance the radiosensitivity of human glioma cells

¹ Molecular Radiation Therapeutics Branch, ² Radiation Oncology Branch, ³ Developmental Therapeutics Program, National Cancer Institute, Bethesda, Maryland and ⁴ Science Applications International Corporation-Frederick, National Cancer Institute-Frederick, Frederick, Maryland

Requests for reprints: Philip J. Tofilon, Radiation Research Program, Molecular Radiation Therapeutics Branch, National Cancer Institute, EPN/6004, 6130 Executive Boulevard, MSC 7440, Rockville, MD 20892-7440. Phone: 301-496-6336; Fax: 301-480-5785. E-mail: tofilonp{at}mail.nih.gov

Akt has been implicated as a molecular determinant of cellular radiosensitivity. Because it is often constitutively activated or overexpressed in malignant gliomas, it has been suggested as a target for brain tumor radiosensitization. To evaluate the role of Akt in glioma radioresponse, we have determined the effects of perifosine, a clinically relevant alkylphospholipid that inhibits Akt activation, on the radiosensitivity of three human glioma cell lines (U87, U251, and LN229). Each of the glioma cell lines expressed clearly detectable levels of phosphorylated Akt indicative of constitutive Akt activity. Exposure to a perifosine concentration that reduced survival by 50% significantly reduced the level of phosphorylated Akt as well as Akt activity. Cell survival analysis using a clonogenic assay, however, revealed that this Akt-inhibiting perifosine treatment did not enhance the radiosensitivity of the glioma cell lines. This evaluation was then extended to an in vivo model using U251 xenografts. Perifosine delivered to mice bearing U251 xenografts substantially reduced tumor phosphorylated Akt levels and inhibited tumor growth rate. However, the combination of perifosine and radiation resulted in a less than additive increase in tumor growth delay. Thus, in vitro and in vivo data indicate that the perifosine-mediated decrease in Akt activity does not enhance the radiosensitivity of three genetically disparate glioma cell lines. These results suggest that, although Akt may influence the radiosensitivity of other tumor types, it does not seem to be a target for glioma cell radiosensitization. [Mol Cancer Ther 2006;5(6):1504–10]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: NCI-Frederick is accredited by Association for Assessment and Accreditation of Laboratory Animal Care International and follows the USPHS Policy on the Care and Use of Laboratory Animals. Animal care was provided in accordance with the procedures outlined in the Guide for Care and Use of Laboratory Animals (NIH publication no. 86-23, 1985).

Received 2/17/06; revised 4/19/06; accepted 4/28/06.

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