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The potential of TRAIL for cancer chemotherapy
M Nagane1, H J Huang, W K Cavenee
1Department of Neurosurgery, Kyorin University School of Medicine, Mitaka, Tokyo, Japan. mnagane@kyorin-u.ac.jp
Abstract:
Innate and acquired resistance to chemotherapy and radiation therapy has been a major obstacle for clinical oncology. One potential adjunct to such conventional treatments is direct induction of cell death by activation of death receptor-mediated apoptosis. TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand), a recently identified member of the growing TNF superfamily, binds to its cognate "death" receptors DR4 and DR5 as well as "decoy" receptors DcR1 and DcR2. Upon binding, rapid apoptosis is enacted in a variety of human cancer cell lines independent of p53 status, but not in normal cell lines. TRAIL treatment results in significant growth suppression of TRAIL-sensitive human cancer xenografts in mice. Furthermore, combination treatment of TRAIL with genotoxic chemotherapeutic agents synergistically suppresses growth of tumor xenografts which are otherwise resistant to treatment with TRAIL or chemotherapy alone. Unlike the other death ligands TNF-alpha or FasL, systemic administration of soluble human TRAIL does not cause toxicity in mice and non-human primates. While further studies are needed to evaluate the possible cytotoxicity of TRAIL especially for human hepatocytes, indications are increasing that TRAIL may be a novel therapeutic agent for human cancer.
Insights
Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) effectively induces cancer cell death and suppresses tumor growth. TRAIL shows promise as a novel cancer therapeutic, especially when combined with chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Cancer treatment resistance to chemotherapy and radiation is a significant clinical challenge.
- Targeting programmed cell death pathways, such as apoptosis, offers a potential therapeutic strategy.
- Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a novel protein that triggers apoptosis.
Purpose of the Study:
- To investigate the efficacy of TRAIL as a standalone and combination therapy for cancer.
- To evaluate the safety and therapeutic potential of TRAIL in preclinical models.
Main Methods:
- Treatment of human cancer cell lines and xenografts with TRAIL.
- Combination therapy studies involving TRAIL and chemotherapeutic agents.
- Toxicity assessments in animal models (mice and non-human primates).
Main Results:
- TRAIL induced rapid apoptosis in various human cancer cell lines, irrespective of p53 status.
- TRAIL treatment significantly suppressed the growth of human cancer xenografts in mice.
- Combination therapy with TRAIL and chemotherapy demonstrated synergistic tumor growth suppression in resistant xenografts.
- Systemic administration of soluble TRAIL showed no significant toxicity in mice and non-human primates.
Conclusions:
- TRAIL is a potent inducer of cancer cell apoptosis and exhibits significant anti-tumor activity.
- TRAIL, particularly in combination with chemotherapy, represents a promising therapeutic strategy for overcoming treatment resistance.
- TRAIL demonstrates a favorable safety profile in preclinical studies, suggesting its potential as a novel cancer therapeutic agent.