Inhibition of Akt by the alkylphospholipid perifosine does not enhance the radiosensitivity of human glioma cells
Molecular Radiation Therapeutics Branch, National Cancer Institute, Bethesda, MD, USA. Molecular Cancer Therapeutics
(Impact Factor: 5.68).
07/2006; 5(6):1504-10. DOI: 10.1158/1535-7163.MCT-06-0091
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 approximately 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.
Available from: Wim van Blitterswijk
- "A discrepancy between in vitro and in vivo radiosensitization was shown in the notoriously radioresistant malignant glioma tumor model. Although De la Pena and coworkers showed clear radiosensitization by perifosine in vitro, subcutaneous gliomas did not show enhanced response to radiation after treatment with perifosine . Becuase only one dose schedule was used, it remains uncertain whether an increased radiation response by perifosine might be obtained at optimal (i.e. "
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ABSTRACT: Our improved understanding of the molecular processes that determine cellular sensitivity to ionizing radiation has accelerated the identification of new targets for intervention. Indeed, novel agents have become available for combined clinical use to overcome radioresistance and increase the therapeutic ratio of radiotherapy. Synthetic alkyl-phospholipid analogs (APLs), such as edelfosine, ilmofosine, miltefosine, perifosine and erucylphosphocholine, are a novel class of anti-tumor agents that target cell membranes to induce growth arrest and apoptosis. In addition, APLs strongly enhance the cytotoxic effect of radiation in preclinical models making these compounds attractive candidates as clinical radiosensitizers. In this review, we will discuss mechanisms of action underlying the rationale to combine APLs with radiotherapy and highlight the clinical perspective of this novel combined modality treatment.
Available from: jpet.aspetjournals.org
- "Almost all of these studies, however, examine the effect of pretreatment or cotreatment of PI3K inhibitors with cytotoxic agents including gIR. Surprisingly, some investigators observed protection or the lack of sensitization to IR-induced cell death when tumor cells were either pretreated or cotreated with PI3K inhibitors (de la Peña et al., 2006;Firat et al., 2012). Thus, the PI3K inhibitors LY294002 and PI-103 were shown to protect cancer stem cells, which have an activated Akt pathway, from low gIR doses primarily by reducing apoptosis (Firat et al., 2012). "
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ABSTRACT: Ionizing radiation (IR) induces genotoxic stress that triggers adaptive cellular responses, such as activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling cascade. Pluripotent cells are the most important population affected by IR because they are required for cellular replenishment. Despite the clear danger to large population centers, we still lack safe and effective therapies to abrogate the life-threating effects of any accidental or intentional IR exposure. Therefore, we computationally analyzed the chemical structural similarity of previously published small molecules that, when given after IR, mitigate cell death and found one chemical cluster that was populated with PI3K inhibitors. Subsequently, we evaluated structurally diverse PI3K inhibitors. Remarkably, 9 of 14 PI3K inhibitors mitigated γIR-induced death in pluripotent NCCIT cells as measured by caspase 3/7 activation. A single i.p. dose of LY294002, administered to mice 4 or 24 h, or PX-867, administered 4 h after a lethal dose of γIR, significantly (p<0.02) enhanced in vivo survival. Because cell cycle checkpoints are important regulators of cell survival after IR, we examined cell cycle distribution in NCCIT cells after γIR and PI3K inhibitor treatment. LY294002 and PX-867 treatment of nonirradiated cells produced a marked decrease in S phase cells with a concomitant increase in the G1 population. In irradiated cells, LY294002 and PX-867 treatment also decreased S phase and increased the G1 and G2 populations. Treatment with LY294002 or PX-867 decreased γIR-induced DNA damage as measured by γH2AX, suggesting reduced DNA damage. These results indicate pharmacological inhibition of PI3K after IR abrogated cell death.
Available from: Guido Henke
- "In line with our findings a recent study showed growth inhibitory effects of treatment with the closely related Perifosine in another glioma xenograft model (U251). Since the growth delay described by the authors was more pronounced compared to the results obtained in our study we speculate that the higher cumulative dose (475 mg/kg) of Perifosine upon oral administration may be responsible for the improved drug action . Similarly, Li et al.  detected a substantial growth delay in neuroblastoma xenograft tumours in nude mice upon a 30-day treatment with Perifosine. "
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Erufosine is a promising anticancer drug that increases the efficacy of radiotherapy in glioblastoma cell lines in vitro. Moreover, treatment of nude mice with repeated intraperitoneal or subcutaneous injections of Erufosine is well tolerated and yields drug concentrations in the brain tissue that are higher than the concentrations required for cytotoxic drug effects on glioblastoma cell lines in vitro.
In the present study we aimed to evaluate the effects of a combined treatment with radiotherapy and Erufosine on growth and local control of T98G subcutaneous glioblastoma xenograft-tumours in NMRI nu/nu mice.
We show that repeated intraperitoneal injections of Erufosine resulted in a significant drug accumulation in T98G xenograft tumours on NMRI nu/nu mice. Moreover, short-term treatment with 5 intraperitoneal Erufosine injections caused a transient decrease in the growth of T98G tumours without radiotherapy. Furthermore, an increased radiation-induced growth delay of T98G xenograft tumours was observed when fractionated irradiation was combined with short-term Erufosine-treatment. However, no beneficial drug effects on fractionated radiotherapy in terms of local tumour control were observed.
We conclude that short-term treatment with Erufosine is not sufficient to significantly improve local control in combination with radiotherapy in T98G glioblastoma xenograft tumours. Further studies are needed to evaluate efficacy of extended drug treatment schedules.
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