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Radio-responsive TRAIL gene therapy for malignant gliomas

Cancer Gene Therapy volume 14, page 1002 (2007)Cite this article

We read with interest the 1 June, 2007 article by Tsurushima et al.1 reporting a novel strategy for the treatment of malignant gliomas that combined tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy and radiation therapy (RT). For this purpose, a plasmid pE4-TRAIL was constructed that included the radio-inducible early growth response gene 1 (Egr-1) promoter, and was tested using U251 and U87 glioma cells. The authors reported that the combination of pE4-TRAIL and RT exhibited synergistic cell death associated with upregulation of death receptors in cells with wild-type p53 expression.

TRAIL has been shown to selectively kill tumor cells by inducing the apoptosis-specific receptors, TRAIL-R1 and TRAIL-R2.2 We have previously reported, in glioma cell lines, that the apoptosis in response to TRAIL may be unrelated to TRAIL-R2 expression but to the activation of the extrinsic (cleavage of caspase-8, caspase-3 and PARP) and mitochondrial apoptotic pathways. Furthermore, TRAIL treatment resulted in neutralization of the Akt pathway, which has been implicated in the resistance to TRAIL-induced apoptosis.3 Taken together, our previous results and the recent study1 indicate that the role of the upregulation of the TRAIL-R1 and TRAIL-R2 in the induction of apoptosis during TRAIL treatment is not clear yet. Nevertheless, we have constructed a recombinant replication-deficient adenovirus vector carrying the TRAIL-R2 cDNA, which may be able to answer these questions. It would be interesting to see if the overexpression of TRAIL-R2 induced by this adenovirus has an additional effect to the combination of pE4-TRAIL and RT in glioma cells, independently on the p53 status.

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References

  1. Tsurushima H, Yuan X, Dillehay LE, Leong KW . Radioresponsive tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene therapy for malignant brain tumors. Cancer Gene Ther 2007; 14: 706–716.

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  2. Falschlehner C, Emmerich CH, Gerlach B, Walczak H . TRAIL signalling: decisions between life and death. Int J Biochem Cell Biol 2007; 39: 1462–1475.

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  3. Puduvalli VK, Sampath D, Bruner JM, Nangia J, Xu R, Kyritsis AP . TRAIL-induced apoptosis in gliomas is enhanced by Akt-inhibition and is independent of JNK activation. Apoptosis 2005; 10: 233–243.

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Authors and Affiliations

  1. Department of Neurology, University Hospital of Ioannina, Ioannina, Greece

    A P Kyritsis

  2. Neurosurgical Institute, University of Ioannina, Ioannina, Greece

    A P Kyritsis

  3. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

    J S Rao

  4. Department of Neuro-oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. E-mail: thkyrits@uoi.gr,

    V K Puduvalli

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  1. A P Kyritsis
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  2. J S Rao
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  3. V K Puduvalli
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Kyritsis, A., Rao, J. & Puduvalli, V. Radio-responsive TRAIL gene therapy for malignant gliomas. Cancer Gene Ther 14, 1002 (2007). https://doi.org/10.1038/sj.cgt.7701083

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