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Antiangiogenic systemic gene therapy combined with doxorubicin administration induced caspase 8 and 9-mediated apoptosis in endothelial cells and an anti-metastasis effect

Cancer Gene Therapy volume 15, pages 535–542 (2008)Cite this article

Abstract

Ad-PPE-Fas-c is an adenovector that expresses Fas-c under the control of the modified pre-proendothelin-1 (PPE-1) promoter. Fas-c is a chimeric death receptor containing the extracellular portion of tumour necrosis factor 1 receptor (TNFR1) and the transmembrane and intracellular portion of Fas. We recently demonstrated that Ad-PPE-Fas-c induced Fas-receptor-mediated endothelial cell apoptosis. Previously, doxorubicin was shown to enhance Fas-receptor clustering and the induction of its cascade. Therefore, the goal of this work was to test whether doxorubicin augments the capacity of Ad-PPE-Fas-c to induce endothelial cell apoptosis and to elucidate whether either the death-receptor-mediated apoptotic cascade or the mitochondria-associated apoptotic cascade is involved in the combined treatment effect. We found that a combined treatment of Ad-PPE-Fas-c and doxorubicin synergistically induced a reduction in endothelial cell viability and apoptosis. z-IETD-FMK, a caspase-8 inhibitor, and z-LEHD-FMK, a caspase-9 inhibitor, significantly decreased apoptosis induced by the combined treatment. Systemically administered combined therapy significantly reduced the lung metastases burden (70%) in mice as compared to each treatment alone. Thus, a combined treatment of Ad-PPE-Fas-c gene therapy and chemotherapy may be effective in the treatment of metastatic diseases and both the Fas cascade and the mitochondria-associated cascade are essential for this effect.

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Authors and Affiliations

  1. Vascular Biogenics Ltd., Or Yehuda, Israel

    M Peled, A Shaish, S Greenberger, I Hodish, I Barshack, I Mendel, L Frishman, R Tal, L Bangio, E Breitbart & D Harats

  2. The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel Hashomer, Israel

    M Peled, A Shaish, S Greenberger, A Katav, I Hodish, D Ben-Shushan, L Frishman, R Tal & D Harats

  3. Department of Clinical Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    M Peled

  4. The Institute of Pathology, Sheba Medical Center, Tel-Hashomer, Israel

    I Barshack

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  1. M Peled
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  2. A Shaish
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Correspondence to D Harats.

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Peled, M., Shaish, A., Greenberger, S. et al. Antiangiogenic systemic gene therapy combined with doxorubicin administration induced caspase 8 and 9-mediated apoptosis in endothelial cells and an anti-metastasis effect. Cancer Gene Ther 15, 535–542 (2008). https://doi.org/10.1038/cgt.2008.20

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  • DOI: https://doi.org/10.1038/cgt.2008.20

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