Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity. - Cancéropôle du Grand Est Accéder directement au contenu
Article Dans Une Revue Cancer Research Année : 2010

Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity.

Résumé

Ongoing clinical trials are exploring anticancer approaches based on signaling by TRAIL, a ligand for the cell death receptors DR4 and DR5. In this study, we report on the selective apoptotic effects of multivalent DR5 binding peptides (TRAIL(mim/DR5)) on cancer cells in vitro and in vivo. Surface plasmon resonance revealed up to several thousand-fold increased affinities of TRAIL(mim/DR5)-receptor complexes on generation of divalent and trivalent molecules, the latter of which was achieved with a conformationally restricted adamantane core. Notably, only multivalent molecules triggered a substantial DR5-dependent apoptotic response in vitro. In tumor models derived from human embryonic kidney cells or primary foreskin fibroblasts, TRAIL(mim/DR5) peptides exerted a cancer cell-selective action that could synergize with resveratrol in a manner independent of p53. In a xenograft model of human colon cancer, a divalent TRAIL(mim/DR5) peptide inhibited tumor growth. Our results offer a proof-of-principle for the development of synthetic small molecules to trigger the TRAIL apoptosis pathway for cancer therapy. Cancer Res; 70(3); 1101-10.

Dates et versions

hal-00451170 , version 1 (28-01-2010)

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Citer

Valeria Pavet, Julien Beyrath, Christophe Pardin, Alexandre Morizot, Marie-Charlotte Lechner, et al.. Multivalent DR5 Peptides Activate the TRAIL Death Pathway and Exert Tumoricidal Activity.. Cancer Research, 2010, 70 (3), pp.1101-1110. ⟨10.1158/0008-5472.CAN-09-2889⟩. ⟨hal-00451170⟩
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