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PMID: 18403709 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models.

Science (New York, N.Y.) ·Vol. 320 ·No. 5873 ·2008-04-11 ·Pages 226-30

Burdelya LG, Krivokrysenko VI, Tallant TC, Strom E, Gleiberman AS, Gupta D, Kurnasov OV, Fort FL, Osterman AL, Didonato JA, Feinstein E, Gudkov AV

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.

MeSH Terms
Amino Acid Sequence Animals Apoptosis/drug effects,radiation effects Chemotherapy, Adjuvant Flagellin/chemistry,pharmacology Gamma Rays Hematopoietic System/drug effects,radiation effects Intestine, Small/cytology,drug effects,radiation effects Macaca mulatta Mice Mice, Inbred ICR Molecular Sequence Data NF-kappa B/metabolism Neoplasms, Experimental/drug therapy,radiotherapy Peptides/administration & dosage,chemistry,pharmacology,toxicity Radiation Dosage Radiation Injuries, Experimental/prevention & control Radiation Tolerance/drug effects Radiation-Protective Agents/administration & dosage,chemistry,pharmacology,toxicity Salmonella enterica Signal Transduction Toll-Like Receptor 5/agonists,metabolism Whole-Body Irradiation
Chemicals
CBLB502 NF-kappa B Peptides Radiation-Protective Agents Toll-Like Receptor 5 Flagellin
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Burdelya Lyudmila G
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Krivokrysenko Vadim I
Tallant Thomas C
Strom Evguenia
Gleiberman Anatoly S
Gupta Damodar
Kurnasov Oleg V
Fort Farrel L
Osterman Andrei L
Didonato Joseph A
Feinstein Elena
Gudkov Andrei V
References (34)
34 references, click to expand
  1. The role of p53 in determining sensitivity to radiotherapy.
    Nat Rev Cancer. 2003 Feb;3(2):117-29 PMID: 12563311
  2. Cloning and characterization of the murine toll-like receptor 5 (Tlr5) gene: sequence and mRNA expression studies in Salmonella-susceptible MOLF/Ei mice.
    Genomics. 2000 Mar 15;64(3):230-40 PMID: 10756091
  3. Abrogation of radiation injury to human hematopoietic stem cells with tumor necrosis factor-alpha.
    Stem Cells. 1997;15 Suppl 2:95-102 PMID: 9368291
  4. Effect of in vivo administration of IL-3 and IL-6, alone and in combination with G-CSF, GM-CSF or IL-1, on haematopoiesis, graft-versus-host disease and survival after murine haematopoietic stem cell transplantation.
    Cytokines Mol Ther. 1995 Mar;1(1):47-55 PMID: 9384663
  5. Activation of nuclear factor kappaB In vivo selectively protects the murine small intestine against ionizing radiation-induced damage.
    Cancer Res. 2004 Sep 1;64(17):6240-6 PMID: 15342410
  6. Toll-like receptors: linking innate and adaptive immunity.
    Adv Exp Med Biol. 2005;560:11-8 PMID: 15932016
  7. Immunogenic chemotherapy: discovery of a critical protein through proteomic analyses of tumor cells.
    Cancer Genomics Proteomics. 2007 Mar-Apr;4(2):65-70 PMID: 17804868
  8. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.
    Cell. 2004 Jul 23;118(2):229-41 PMID: 15260992
  9. Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53 suppression in tumors.
    Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17448-53 PMID: 16287968
  10. Manganese superoxide dismutase (SOD2) inhibits radiation-induced apoptosis by stabilization of the mitochondrial membrane.
    Radiat Res. 2002 May;157(5):568-77 PMID: 11966323
  11. Radiation and ceramide-induced apoptosis.
    Oncogene. 2003 Sep 1;22(37):5897-906 PMID: 12947396
  12. Effects of flagellin on innate and adaptive immunity.
    Immunol Res. 2005;33(1):83-101 PMID: 16120974
  13. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy.
    Science. 1999 Sep 10;285(5434):1733-7 PMID: 10481009
  14. Protection against ionizing radiation by antioxidant nutrients and phytochemicals.
    Toxicology. 2003 Jul 15;189(1-2):1-20 PMID: 12821279
  15. Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells.
    Nat Immunol. 2006 Aug;7(8):868-74 PMID: 16829963
  16. Altered epithelial cell lineage allocation and global expansion of the crypt epithelial stem cell population are associated with ileitis in SAMP1/YitFc mice.
    Am J Pathol. 2005 Apr;166(4):1055-67 PMID: 15793286
  17. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice.
    Science. 2001 Jul 13;293(5528):293-7 PMID: 11452123
  18. 5-androstenediol improves survival in clinically unsupported rhesus monkeys with radiation-induced myelosuppression.
    Int Immunopharmacol. 2007 Apr;7(4):500-5 PMID: 17321473
  19. Dual effect of p53 on radiation sensitivity in vivo: p53 promotes hematopoietic injury, but protects from gastro-intestinal syndrome in mice.
    Oncogene. 2004 Apr 22;23(19):3265-71 PMID: 15064735
  20. TLR5-mediated phosphoinositide 3-kinase activation negatively regulates flagellin-induced proinflammatory gene expression.
    J Immunol. 2006 May 15;176(10):6194-201 PMID: 16670329
  21. Colony-stimulating factors for the management of neutropenia in cancer patients.
    Drugs. 2002;62 Suppl 1:1-15 PMID: 12479591
  22. p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis.
    Nat Genet. 1994 Sep;8(1):66-9 PMID: 7987394
  23. Human intestinal microvascular endothelial cells express Toll-like receptor 5: a binding partner for bacterial flagellin.
    J Immunol. 2004 Apr 15;172(8):5056-62 PMID: 15067088
  24. Cytokine overexpression and constitutive NFkappaB in cancer.
    Cell Cycle. 2004 Sep;3(9):1114-7 PMID: 15492502
  25. Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention.
    Biochem Pharmacol. 2004 Sep 15;68(6):1089-100 PMID: 15313405
  26. Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group.
    Ann Intern Med. 2004 Jun 15;140(12):1037-51 PMID: 15197022
  27. Nuclear factor-kappaB in cancer development and progression.
    Nature. 2006 May 25;441(7092):431-6 PMID: 16724054
  28. The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice.
    Cancer Metastasis Rev. 1992 Sep;11(2):179-95 PMID: 1394796
  29. Pharmacologic approaches to protection against radiation-induced lethality and other damage.
    Environ Health Perspect. 1997 Dec;105 Suppl 6:1473-8 PMID: 9467066
  30. Flagellin, a novel mediator of Salmonella-induced epithelial activation and systemic inflammation: I kappa B alpha degradation, induction of nitric oxide synthase, induction of proinflammatory mediators, and cardiovascular dysfunction.
    J Immunol. 2001 Jan 15;166(2):1248-60 PMID: 11145708
  31. Flagellin acting via TLR5 is the major activator of key signaling pathways leading to NF-kappa B and proinflammatory gene program activation in intestinal epithelial cells.
    BMC Microbiol. 2004 Aug 23;4:33 PMID: 15324458
  32. Androstenediol stimulates myelopoiesis and enhances resistance to infection in gamma-irradiated mice.
    Int J Immunopharmacol. 2000 Jan;22(1):1-14 PMID: 10684984
  33. Role of cytokines (interleukin 1, tumor necrosis factor, and transforming growth factor beta) in natural and lipopolysaccharide-enhanced radioresistance.
    J Exp Med. 1991 May 1;173(5):1177-82 PMID: 2022925
  34. Identification of conserved domains in Salmonella muenchen flagellin that are essential for its ability to activate TLR5 and to induce an inflammatory response in vitro.
    J Biol Chem. 2004 Feb 13;279(7):5667-75 PMID: 14634022
Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.1154986
Published
2008-04-11
Pages
226-30
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC4322935
Subset
IM
Grants
NCI NIH HHS · CA75179 · United States
NCI NIH HHS · R01 CA075179 · United States
NCI NIH HHS · CA84406 · United States
NIAID NIH HHS · R01 AI066497 · United States
NCI NIH HHS · R01 CA084406 · United States
NCI NIH HHS · R01 CA084406-01A1 · United States
NIAID NIH HHS · AI066497 · United States
Corrections
CommentIn
PMID: 18403680
External Links
PubMed source DOI: 10.1126/science.1154986 PMC Full Text View journal details
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