An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models.
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.
Burdelya
Lyudmila G
LG
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Krivokrysenko
Vadim I
VI
Tallant
Thomas C
TC
Strom
Evguenia
E
Gleiberman
Anatoly S
AS
Gupta
Damodar
D
Kurnasov
Oleg V
OV
Fort
Farrel L
FL
Osterman
Andrei L
AL
Didonato
Joseph A
JA
Feinstein
Elena
E
Gudkov
Andrei V
AV
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D017024:Chemotherapy, Adjuvant; D005408:Flagellin / Q000737:chemistry / Q000494:pharmacology; D005720:Gamma Rays; D006413:Hematopoietic System / Q000187:drug effects / Q000528:radiation effects; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008253:Macaca mulatta; D051379:Mice; D008813:Mice, Inbred ICR; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011836:Radiation Tolerance / Q000187:drug effects*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D019779:Salmonella enterica; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000819:agonists* / Q000378:metabolism; D014916:Whole-Body Irradiation
C528306:CBLB502; D016328:NF-kappa B; D010455:Peptides; D011837:Radiation-Protective Agents; D051198:Toll-Like Receptor 5; D005408:Flagellin