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

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 p...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2010-02, Vol.70 (3), p.1101-1110
Hauptverfasser: PAVET, Valeria, BEYRATH, Julien, GUICHARD, Gilles, GRONEMEYER, Hinrich, PARDIN, Christophe, MORIZOT, Alexandre, LECHNER, Marie-Charlotte, BRIAND, Jean-Paul, WENDLAND, Miriam, MAISON, Wolfgang, FOURNEL, Sylvie, MICHEAU, Olivier
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Sprache:eng
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Zusammenfassung: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-09-2889