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Potential and caveats of TRAIL in cancer therapy
1Department of Immunology and Cell Biology, University of Münster, Münster, Germany.
Abstract:
Induction of apoptosis in tumor cells is a major goal for chemotherapy and radiation treatment strategies. However, disordered gene expression often leads to apoptosis resistance rendering tumor cells insensitive to various conventional treatments. TNF-related apoptosis-inducing ligand (TRAIL) is a recently identified cytokine of the TNF superfamily that induces apoptosis in tumor cells upon binding to different receptors. Remarkably, the majority of tumor cell lines are sensitive to TRAIL-induced apoptosis, while most nontransformed cell types are TRAIL-resistant. Furthermore, a combination treatment of TRAIL with ionizing irradiation or chemotherapeutic agents induces apoptosis in a highly synergistic manner, particularly in those cells that are otherwise resistant to a sole treatment. In contrast to other TNF members, TRAIL apparently does not exert overt systemic toxicity in murine and primate models, although unexpected concerns about a potential hepatotoxicity of TRAIL have been recently raised. While the molecular mechanisms of TRAIL sensitivity and resistance are poorly understood, TRAIL seems to be a promising biological agent for combination therapy with chemotherapeutic drugs or irradiation.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively induces cancer cell death and shows promise in combination therapies. TRAIL demonstrates tumor selectivity, offering a potential new avenue for cancer treatment strategies.
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- Apoptosis induction is a key goal in cancer chemotherapy and radiation therapy.
- Apoptosis resistance in tumor cells, often due to disordered gene expression, limits conventional treatment efficacy.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that triggers apoptosis in tumor cells.
Purpose of the Study:
- To investigate the potential of TRAIL as a therapeutic agent for cancer treatment.
- To evaluate TRAIL's efficacy in inducing apoptosis in tumor cells, particularly in combination therapies.
Main Methods:
- Analysis of TRAIL's ability to induce apoptosis in various tumor cell lines.
- Assessment of TRAIL's synergistic effects when combined with ionizing irradiation or chemotherapeutic agents.
- Evaluation of TRAIL's systemic toxicity in preclinical models (murine and primate).
Main Results:
- Most tumor cell lines are sensitive to TRAIL-induced apoptosis, while most normal cells are resistant.
- Combination therapy with TRAIL and conventional treatments shows significant synergistic apoptosis induction, even in resistant cells.
- TRAIL exhibits minimal systemic toxicity in animal models, though potential hepatotoxicity warrants further investigation.
Conclusions:
- TRAIL is a promising biological agent for cancer therapy due to its tumor-selective apoptosis-inducing properties.
- Combination strategies involving TRAIL with chemotherapy or radiation demonstrate enhanced efficacy.
- Further research into TRAIL's mechanisms of action and safety profile is warranted for clinical application.