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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis / drug effects
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Apoptosis / radiation effects
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Chemotherapy, Adjuvant
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Flagellin / chemistry
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Flagellin / pharmacology
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Gamma Rays
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Hematopoietic System / drug effects
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Hematopoietic System / radiation effects
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Intestine, Small / cytology
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Intestine, Small / drug effects
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Intestine, Small / radiation effects
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Macaca mulatta
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Mice
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Mice, Inbred ICR
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Molecular Sequence Data
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NF-kappa B / metabolism*
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / radiotherapy
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Peptides / administration & dosage
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Peptides / chemistry
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Peptides / pharmacology*
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Peptides / toxicity
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Radiation Dosage
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Radiation Injuries, Experimental / prevention & control*
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Radiation Tolerance / drug effects*
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Radiation-Protective Agents / administration & dosage
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Radiation-Protective Agents / chemistry
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Radiation-Protective Agents / pharmacology*
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Radiation-Protective Agents / toxicity
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Salmonella enterica
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Signal Transduction
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Toll-Like Receptor 5 / agonists*
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Toll-Like Receptor 5 / metabolism
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Whole-Body Irradiation
Substances
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CBLB502
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NF-kappa B
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Peptides
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Radiation-Protective Agents
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Toll-Like Receptor 5
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Flagellin