Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model.
Melanoma is a highly metastatic and deadly form of cancer. Invasive melanoma cells overexpress integrin $\alpha$v$\beta$3, which is a well-known target for Arg-Gly-Asp-based (RGD) peptides. We developed a sophisticated method to synthesize milligram amts. 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 $μ$M 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 i.v. injection in a human melanoma tumor model established in humanized immuno-competent mice. In addn. 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. [on SciFinder(R)]
Références
- Titre
- Systemic Delivery of Tumor-Targeted Bax-Derived Membrane-Active Peptides for the Treatment of Melanoma Tumors in a Humanized SCID Mouse Model.
- Type de publication
- Article de revue
- Année de publication
- 2017
- Auteurs
- Karageorgis, Anastassia, Claron Michael, Juge Romain, Aspord Caroline, Thoreau Fabien, Leloup Claire, Kucharczak Jerome, Plumas Joel, Henry Maxime, Hurbin Amandine, Verdie Pascal, Martinez Jean, Subra Gilles, Dumy Pascal, Boturyn Didier, Aouacheria Abdel, and Coll Jean-Luc.
- Revue
- Mol. Ther.
- Volume
- 25
- Pagination
- 534–546
- ISSN
- 1525-0024
Soumis le 12 avril 2018