An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models

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.

Toll-like Receptor 5 Agonist Inhibition of Growth of A549 Lung Cancer Cells in Vivo in a Myd88 Dependent Manner

“…Recent study has shown that the activation of TLR5 by CBLB502 possesses radioprotective activity in mouse and primate models (Burdelya et al, 2008). More importantly, CBLB502 has no radioprotective effect on the tumors when it is administrated to tumor-bearing mouse treated with radiotherapy.…”

“…CBLB502, a kind of polypeptide drug derived from Salmonella flagellin, can bind to TLR5 specifically and activate NF-kB signaling. Furthermore, it has been reported that CBLB502 has radioprotective activity in mouse and primate models (Burdelya et al, 2008).…”

Nuclear Factor κB Inhibitors Alleviate and the Proteasome Inhibitor PS-341 Exacerbates Radiation Toxicity in Zebrafish Embryos

“…Interestingly, radiation protection of zebrafish embryos by NF-κB inhibitors extended to the gastrointestinal system whereas previous work using genetically modified mice 42 and the TLR5 ligand flagellin 43 has implicated NF-κB activation in radiation protection of gastrointestinal stem cells. The reason(s) for this difference are unclear at this point.…”

“…This was done in consideration of several prior reports suggesting that NF-κB activation protects the gastrointestinal tract of higher vertebrates against acute radiation damage. 42,43 Radiation protection of the gastrointestinal system was determined in several ways. First, we assayed overall gastrointestinal function by scoring "long-term" survival of fish irradiated in the presence and absence of EP or CDDO-TFEA (up to 15 dpf).…”

324 Epithelial Cell Specific MyD88 Signaling Mediates Ischemia/Reperfusion-Induced Intestinal Injury Independent of Microbial Status

“…10 Interestingly, the microbiota seems to play a protective role in various experimental injury models including dextran sodium sulfate and radiation. [11][12][13] In contrast, global deletion of myeloid differentiation primary response gene (Myd88), an adaptor protein in innate immune signaling, protects mice from I/R-induced injury. 14 Moreover, in a model of necrotizing enterocolitis in newborn mice, TLR/MyD88-mediated intestinal injury seems to be controlled by nucleotide-binding oligomerization domain-2 signaling.…”