Karageorgis, A;
Claron, M;
Juge, R;
Aspord, C;
Thoreau, F;
Leloup, C;
Kucharczak, J;
... Coll, J-L; + view all
(2017)
Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model.
Molecular Therapy
, 25
(2)
pp. 534-546.
10.1016/j.ymthe.2016.11.002.
Preview |
Text
Thoreau_1-s2.0-S1525001616453852-main.pdf - Published Version Download (3MB) | Preview |
Abstract
Melanoma is a highly metastatic and deadly form of cancer. Invasive melanoma cells overexpress integrin αvβ3, which is a well-known target for Arg-Gly-Asp-based (RGD) peptides. We developed a sophisticated method to synthetize milligram amounts of a targeted vector that allows the RGD-mediated targeting, internalization, and release of a mitochondria-disruptive peptide derived from the pro-apoptotic Bax protein. We found that 2.5 μM Bax[109-127] was sufficient to destabilize the mitochondria in ten different tumor cell lines, even in the presence of the anti-apoptotic Bcl2 protein, which is often involved in tumor resistance. This pore-forming peptide displayed antitumor activity when it was covalently linked by a disulfide bridge to the tetrameric RAFT-c[RGD]4-platform and after intravenous injection in a human melanoma tumor model established in humanized immuno-competent mice. In addition to its direct toxic effect, treatment with this combination induced the release of the immuno-stimulating factor monocyte chimoattractant protein 1 (MCP1) in the blood and a decrease in the level of the pro-angiogenic factor FGF2. Our novel multifunctional, apoptosis-inducing agent could be further customized and assayed for potential use in tumor-targeted therapy.
| Type: | Article |
|---|---|
| Title: | Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ymthe.2016.11.002 |
| Publisher version: | https://doi.org/10.1016/j.ymthe.2016.11.002 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biotechnology & Applied Microbiology, Genetics & Heredity, Medicine, Research & Experimental, Research & Experimental Medicine, ALPHA(V)BETA(3) INTEGRIN, CY5-LABELED RAFT-C(-RGDFK-)(4), ALPHA-V-BETA-3 INTEGRIN, HUMAN PROSTATE, BREAST-CANCER, RGD PEPTIDES, GROWTH, MITOCHONDRIA, CELLS, MICE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10092113 |
Archive Staff Only
 |
View Item |
