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Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity
Valeria Pavet1, Julien Beyrath, Christophe Pardin
1Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 10142, Illkirch, France.
Cancer Research
|January 28, 2010
Summary
Multivalent peptides targeting DR5 selectively induce cancer cell death via the TRAIL apoptosis pathway. These synthetic molecules show promise for novel cancer therapies, demonstrating effectiveness in preclinical models.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway is a target for cancer therapy.
- Developing selective agonists for TRAIL death receptors (DR4 and DR5) is crucial.
Purpose of the Study:
- To investigate the selective apoptotic effects of multivalent DR5-binding peptides (TRAIL(mim/DR5)) on cancer cells.
- To evaluate the therapeutic potential of these synthetic molecules in preclinical cancer models.
Main Methods:
- Surface plasmon resonance was used to determine binding affinities of TRAIL(mim/DR5) peptides to DR5.
- In vitro assays assessed DR5-dependent apoptosis induction.
- In vivo studies utilized human embryonic kidney cell and primary foreskin fibroblast tumor models, as well as a human colon cancer xenograft model.
Main Results:
- Multivalent TRAIL(mim/DR5) peptides exhibited significantly increased affinities for DR5 compared to monovalent forms.
- Only multivalent peptides induced substantial DR5-dependent apoptosis in vitro.
- TRAIL(mim/DR5) peptides demonstrated cancer cell-selective action in tumor models and synergized with resveratrol independently of p53.
- A divalent TRAIL(mim/DR5) peptide inhibited tumor growth in a human colon cancer xenograft model.
Conclusions:
- Multivalent DR5-binding peptides represent a promising strategy for activating the TRAIL apoptosis pathway.
- These synthetic molecules offer a proof-of-principle for developing novel, selective cancer therapeutics.
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