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 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.
INSERM U1209, Institut Albert Bonniot, 38706 La Tronche, France; Université Grenoble Alpes, 38000 Grenoble, France.
Anastassia
A
Karageorgis
Université Grenoble Alpes, 38000 Grenoble, France; CNRS UMR 5250, ICMG FR2607, 38000 Grenoble, France.
Michaël
M
Claron
Molecular Biology of the Cell Laboratory (LBMC), Ecole Normale Supérieure de Lyon, UMR 5239 CNRS - UCBL - ENS Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07, France.
Romain
R
Jugé
Université Grenoble Alpes, 38000 Grenoble, France; EMR EFS-UGA-INSERM U1209- CNRS, Immunobiology and Immunotherapy of Chronic Diseases, 38706 La Tronche, France; EFS Rhone-Alpes, R&D Laboratory, 38701 La Tronche, France.
Caroline
C
Aspord
INSERM U1209, Institut Albert Bonniot, 38706 La Tronche, France; Université Grenoble Alpes, 38000 Grenoble, France; CNRS UMR 5250, ICMG FR2607, 38000 Grenoble, France.
Fabien
F
Thoreau
Université Grenoble Alpes, 38000 Grenoble, France; EMR EFS-UGA-INSERM U1209- CNRS, Immunobiology and Immunotherapy of Chronic Diseases, 38706 La Tronche, France; EFS Rhone-Alpes, R&D Laboratory, 38701 La Tronche, France.
Claire
C
Leloup
Molecular Biology of the Cell Laboratory (LBMC), Ecole Normale Supérieure de Lyon, UMR 5239 CNRS - UCBL - ENS Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07, France.
Jérôme
J
Kucharczak
Université Grenoble Alpes, 38000 Grenoble, France; EMR EFS-UGA-INSERM U1209- CNRS, Immunobiology and Immunotherapy of Chronic Diseases, 38706 La Tronche, France; EFS Rhone-Alpes, R&D Laboratory, 38701 La Tronche, France.
Joël
J
Plumas
INSERM U1209, Institut Albert Bonniot, 38706 La Tronche, France; Université Grenoble Alpes, 38000 Grenoble, France.
Maxime
M
Henry
INSERM U1209, Institut Albert Bonniot, 38706 La Tronche, France; Université Grenoble Alpes, 38000 Grenoble, France.
Amandine
A
Hurbin
CNRS UMR 5247, Institut des Biomolécules Max Mousseron IBMM, 34095 Montpellier, France.
Pascal
P
Verdié
CNRS UMR 5247, Institut des Biomolécules Max Mousseron IBMM, 34095 Montpellier, France.
Jean
J
Martinez
CNRS UMR 5247, Institut des Biomolécules Max Mousseron IBMM, 34095 Montpellier, France.
Gilles
G
Subra
CNRS UMR 5250, ICMG FR2607, 38000 Grenoble, France; CNRS UMR 5247, Institut des Biomolécules Max Mousseron IBMM, 34095 Montpellier, France.
Pascal
P
Dumy
Université Grenoble Alpes, 38000 Grenoble, France; CNRS UMR 5250, ICMG FR2607, 38000 Grenoble, France.
Didier
D
Boturyn
Molecular Biology of the Cell Laboratory (LBMC), Ecole Normale Supérieure de Lyon, UMR 5239 CNRS - UCBL - ENS Lyon, 46 Allée d'Italie, 69364 Lyon Cedex 07, France; Institut des Sciences de l'Evolution de Montpellier (ISEM), UMR 5554, Université de Montpellier, CNRS, IRD, EPHE, Place Eugène Bataillon, 34095 Montpellier, France. Electronic address: jean-luc.coll@univ-grenoble-alpes.fr.
Abdel
A
Aouacheria
INSERM U1209, Institut Albert Bonniot, 38706 La Tronche, France; Université Grenoble Alpes, 38000 Grenoble, France. Electronic address: abdel.aouacheria@umontpellier.fr.
Jean-Luc
JL
Coll
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000737:chemistry*
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D051028:bcl-2-Associated X Protein
BAX; RGD; pore-forming peptides; targeted delivery