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Efficacy of adenovirally expressed soluble TRAIL in human glioma organotypic slice culture and glioma xenografts.

Liu Y, Lang F, Xie X, Prabhu S, Xu J, Sampath D, Aldape K, Fuller G, Puduvalli VK - Cell Death Dis (2011)

Bottom Line: It inhibited anchorage-independent glioma growth and exerted a bystander effect in transwell assays.Intratumoral injections of AdsTRAIL in a rodent intracranial glioma model resulted in reduced tumor growth and improved survival compared with Ad-enhanced green fluorescent protein (EGFP)- or vehicle-treated controls without toxicity.Human glioma organotypic slices treated with AdsTRAIL demonstrated apoptosis induction and caspase activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuro-oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77035, USA.

ABSTRACT
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in malignant cells, including gliomas, and is currently in anticancer clinical trials. However, the full-length and tagged forms of TRAIL, unlike the untagged ligand (soluble TRAIL (sTRAIL)), exhibits toxicity against normal cells. Here, we report the generation and testing of an adenovirus (AdsTRAIL) that expresses untagged sTRAIL in an intracranial xenograft model and a human glioma organotypic slice culture model. AdsTRAIL efficiently induced apoptosis in glioma cell lines, including those resistant to sTRAIL, but not in normal human astrocytes (NHAs). It inhibited anchorage-independent glioma growth and exerted a bystander effect in transwell assays. Intratumoral injections of AdsTRAIL in a rodent intracranial glioma model resulted in reduced tumor growth and improved survival compared with Ad-enhanced green fluorescent protein (EGFP)- or vehicle-treated controls without toxicity. Human glioma organotypic slices treated with AdsTRAIL demonstrated apoptosis induction and caspase activation.

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Related in: MedlinePlus

(a) Immunoblot analysis of extrinsic death pathway activation including cleavage of caspase 8, caspase 3, and PARP (arrows) in U251HF cells treated with AdsTRAIL or sTRAIL for the periods indicated. Soluble TRAIL (sT)-treated cells were assessed as control. (b) Comparison between the effects of AdsTRAIL (AdsT) or AdEGFP (AdE) upon caspase 8, caspase 3, and PARP in U251HF cells and NHAs. Cells were treated with 100 MOI of adenovirus and harvested at 24 h
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fig2: (a) Immunoblot analysis of extrinsic death pathway activation including cleavage of caspase 8, caspase 3, and PARP (arrows) in U251HF cells treated with AdsTRAIL or sTRAIL for the periods indicated. Soluble TRAIL (sT)-treated cells were assessed as control. (b) Comparison between the effects of AdsTRAIL (AdsT) or AdEGFP (AdE) upon caspase 8, caspase 3, and PARP in U251HF cells and NHAs. Cells were treated with 100 MOI of adenovirus and harvested at 24 h

Mentions: To examine the basis for differential induction of apoptosis by AdsTRAIL in glioma cells, but not NHAs, we studied the components of the extrinsic apoptosis pathway in U251HF cells; activation of caspase 8 and caspase 3 was seen in a time-dependent manner closely paralleled by poly ADP ribose polymerase (PARP) cleavage (Figure 2a). In contrast, NHAs treated with AdsTRAIL at 100 multiplicity of infection (MOI) for 24 h did not show activation of the extrinsic apoptotic pathway (Figure 2b), supporting the possibility that the effects of AdsTRAIL are likely specific to gliomas.


Efficacy of adenovirally expressed soluble TRAIL in human glioma organotypic slice culture and glioma xenografts.

Liu Y, Lang F, Xie X, Prabhu S, Xu J, Sampath D, Aldape K, Fuller G, Puduvalli VK - Cell Death Dis (2011)

(a) Immunoblot analysis of extrinsic death pathway activation including cleavage of caspase 8, caspase 3, and PARP (arrows) in U251HF cells treated with AdsTRAIL or sTRAIL for the periods indicated. Soluble TRAIL (sT)-treated cells were assessed as control. (b) Comparison between the effects of AdsTRAIL (AdsT) or AdEGFP (AdE) upon caspase 8, caspase 3, and PARP in U251HF cells and NHAs. Cells were treated with 100 MOI of adenovirus and harvested at 24 h
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3101700&req=5

fig2: (a) Immunoblot analysis of extrinsic death pathway activation including cleavage of caspase 8, caspase 3, and PARP (arrows) in U251HF cells treated with AdsTRAIL or sTRAIL for the periods indicated. Soluble TRAIL (sT)-treated cells were assessed as control. (b) Comparison between the effects of AdsTRAIL (AdsT) or AdEGFP (AdE) upon caspase 8, caspase 3, and PARP in U251HF cells and NHAs. Cells were treated with 100 MOI of adenovirus and harvested at 24 h
Mentions: To examine the basis for differential induction of apoptosis by AdsTRAIL in glioma cells, but not NHAs, we studied the components of the extrinsic apoptosis pathway in U251HF cells; activation of caspase 8 and caspase 3 was seen in a time-dependent manner closely paralleled by poly ADP ribose polymerase (PARP) cleavage (Figure 2a). In contrast, NHAs treated with AdsTRAIL at 100 multiplicity of infection (MOI) for 24 h did not show activation of the extrinsic apoptotic pathway (Figure 2b), supporting the possibility that the effects of AdsTRAIL are likely specific to gliomas.

Bottom Line: It inhibited anchorage-independent glioma growth and exerted a bystander effect in transwell assays.Intratumoral injections of AdsTRAIL in a rodent intracranial glioma model resulted in reduced tumor growth and improved survival compared with Ad-enhanced green fluorescent protein (EGFP)- or vehicle-treated controls without toxicity.Human glioma organotypic slices treated with AdsTRAIL demonstrated apoptosis induction and caspase activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuro-oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77035, USA.

ABSTRACT
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in malignant cells, including gliomas, and is currently in anticancer clinical trials. However, the full-length and tagged forms of TRAIL, unlike the untagged ligand (soluble TRAIL (sTRAIL)), exhibits toxicity against normal cells. Here, we report the generation and testing of an adenovirus (AdsTRAIL) that expresses untagged sTRAIL in an intracranial xenograft model and a human glioma organotypic slice culture model. AdsTRAIL efficiently induced apoptosis in glioma cell lines, including those resistant to sTRAIL, but not in normal human astrocytes (NHAs). It inhibited anchorage-independent glioma growth and exerted a bystander effect in transwell assays. Intratumoral injections of AdsTRAIL in a rodent intracranial glioma model resulted in reduced tumor growth and improved survival compared with Ad-enhanced green fluorescent protein (EGFP)- or vehicle-treated controls without toxicity. Human glioma organotypic slices treated with AdsTRAIL demonstrated apoptosis induction and caspase activation.

Show MeSH
Related in: MedlinePlus