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

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Pavet, Valeria | Beyrath, Julien | Pardin, Christophe | Morizot, Alexandre | Lechner, Marie-Charlotte | Briand, Jean-Paul | Wendland, Miriam | Maison, Wolfgang | Fournel, Sylvie | Micheau, Olivier | Guichard, Gilles | Gronemeyer, Hinrich

Edité par CCSD ; American Association for Cancer Research -

International audience. 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.

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