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
M PeledDror Harats

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....Continue Reading

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Citations

Sep 18, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Reshef TalDror Harats
Nov 28, 2013·Burns : Journal of the International Society for Burn Injuries·Jinli ZhangChien-an A Hu
Oct 4, 2011·Expert Opinion on Biological Therapy·Pierre L Triozzi, Ernest C Borden
Sep 14, 2011·Expert Opinion on Investigational Drugs·Pamela Jo Harris, Keith C Bible
Apr 17, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Andrew J BrennerPierre L Triozzi

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