Abstract：
: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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Pavet V,Beyrath J,Pardin C,Morizot A,Lechner MC,Briand JP,Wendland M,Maison W,Fournel S,Micheau O,Guichard G,Gronemeyer Hdoi
10.1158/0008-5472.CAN-09-2889subject
Has Abstractpub_date
2010-02-01 00:00:00pages
1101-10issue
3eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-09-2889journal_volume
70pub_type
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