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
Source: PubMed

ABSTRACT 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.

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    • "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 [103]. 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.
    Anti-cancer agents in medicinal chemistry 03/2014; 14(4). DOI:10.2174/1871520614666140309224145 · 2.47 Impact Factor
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    • "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 [22]. Similarly, Li et al. [23] detected a substantial growth delay in neuroblastoma xenograft tumours in nude mice upon a 30-day treatment with Perifosine. "
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    ABSTRACT: Background 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. Methods 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. Results 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. Conclusions 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.
    Radiation Oncology 10/2012; 7(1):172. DOI:10.1186/1748-717X-7-172 · 2.55 Impact Factor
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    • "Among four identified AR downstream signaling pathways (activation of Akt and Wnt signaling and higher expressions of bcl-2 and c-myc) in the PCa stem/progenitor cells, we found few available small molecules in clinical trials that could be used to target Wnt and c-myc effectively. For the Akt and bcl-2, we decided to use g-TT and not the currently available Akt inhibitors in our strategy with the following reasons: (i) g-TT could simultaneously target bcl-2 and Akt signaling, (ii) g-TT could overcome the problem of toxicity of the current available PI3K/Akt inhibitors, such as LY294002 (de la Pena et al., 2006; Markman et al., 2010), and (iii) those current available Akt inhibitors, such as LY294002, might result in an unwanted problem of increasing some PCa cells invasion ability (Chang et al., manuscript in preparation ), even though showing better efficacy to reduce PCa sizes (Hutchinson et al., 2004; Dillon et al., 2009). We are aware of the debates about the effect of long-term supplement of a-Vit E to reduce PCa incidence, and even though g-TT and a-Vit E share some similar structure, these two compounds have totally different functions, with g-TT not a-Vit E, effectively inhibiting the growth of PCa stem/progenitor cells. "
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    ABSTRACT: The androgen deprivation therapy (ADT) to systematically suppress/reduce androgens binding to the androgen receptor (AR) has been the standard therapy for prostate cancer (PCa); yet, most of ADT eventually fails leading to the recurrence of castration resistant PCa. Here, we found that the PCa patients who received ADT had increased PCa stem/progenitor cell population. The addition of the anti-androgen, Casodex(®), or AR-siRNA in various PCa cells led to increased stem/progenitor cells, whereas, in contrast, the addition of functional AR led to decreased stem/progenitor cell population but increased non-stem/progenitor cell population, suggesting that AR functions differentially in PCa stem/progenitor vs. non-stem/progenitor cells. Therefore, the current ADT might result in an undesired expansion of PCa stem/progenitor cell population, which explains why this therapy fails. Using various human PCa cell lines and three different mouse models, we concluded that targeting PCa non-stem/progenitor cells with AR degradation enhancer ASC-J9(®) and targeting PCa stem/progenitor cells with 5-azathioprine and γ-tocotrienol resulted in a significant suppression of the tumors at the castration resistant stage. This suggests that a combinational therapy that simultaneously targets both stem/progenitor and non-stem/progenitor cells will lead to better therapeutic efficacy and may become a new therapy to battle the PCa before and after castration resistant stages.
    Journal of Molecular Cell Biology 07/2012; 5(1). DOI:10.1093/jmcb/mjs042 · 6.77 Impact Factor
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