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Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models
Lyudmila G Burdelya1, Vadim I Krivokrysenko, Thomas C Tallant
1Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Abstract:
The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor-kappaB signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys. Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.
Insights
A novel drug, CBLB502, activates Toll-like receptor 5 (TLR5) signaling to protect healthy cells from radiation toxicity. This radioprotective agent improved survival in mice and monkeys without reducing tumor radiosensitivity.
Area of Science:
- Radiation biology
- Immunology
- Pharmacology
Background:
- Ionizing radiation causes severe toxicity via apoptosis in radiosensitive organs.
- Tumor cells utilize signaling mechanisms to suppress apoptosis, a process that can be targeted.
- CBLB502 is a drug derived from Salmonella flagellin that activates nuclear factor-kappaB signaling through Toll-like receptor 5 (TLR5).
Purpose of the Study:
- To investigate the radioprotective potential of CBLB502 in healthy cells.
- To determine if CBLB502 can mitigate the harmful effects of radiation exposure.
- To assess the impact of CBLB502 on tumor radiosensitivity.
Main Methods:
- Administration of CBLB502 to mice and rhesus monkeys before or after lethal total-body irradiation.
- Evaluation of gastrointestinal and hematopoietic acute radiation syndromes.
- Assessment of survival rates and tumor radiosensitivity in mouse models.
Main Results:
- A single CBLB502 injection before irradiation significantly improved survival in mice by protecting against acute radiation syndromes.
- Post-irradiation CBLB502 administration also enhanced survival, particularly at lower radiation doses.
- CBLB502 demonstrated radioprotective effects in lethally irradiated rhesus monkeys.
- The drug did not reduce tumor radiosensitivity in preclinical models.
Conclusions:
- Toll-like receptor 5 (TLR5) agonists like CBLB502 show promise as radioprotective agents.
- CBLB502 could potentially enhance the therapeutic index of cancer radiotherapy.
- TLR5 agonists may serve as effective biological protectants in radiation emergencies.
