Identification of Granulocyte Colony-Stimulating Factor and Interleukin-6 as Candidate Biomarkers of CBLB502 Efficacy as a Medical Radiation Countermeasure

Krivokrysenko, Vadim I.; Shakhov, Alexander N.; Singh, Vijay K.; Bone, Frederick; Kononov, Yevgeniy; Shyshynova, Inna; Cheney, Alec; Maitra, Ratan K.; Purmal, Andrei A.; Whitnall, Mark H.; Gudkov, Andrei V.; Feinstein, Elena

doi:10.1124/jpet.112.196071

Cited by 99 publications

(110 citation statements)

References 45 publications

(47 reference statements)

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“…This proposed signaling mechanism is supported by structure-guided mutagenesis and the deletion analysis of CBLB502 (11). Granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) are candidate biomarkers of the radioprotective efficacy of CBLB502, and both G-CSF and IL-6 activity is TLR5-dependent and CBLB502 dose-dependent (12). The no-observed adverse effect level (NOAEL) for the developmental toxicity of CBLB502 in Wistar rats was estimated to be ≥300 μg/kg/day (13).…”

Section: Introductionmentioning

confidence: 88%

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CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation

Xu¹,

Dong

et al. 2016

Ann. Transl. Med.

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Background: Ulcerative colitis (UC) is a nonspecific inflammatory disease for which medications and therapeutic strategies have only been moderately successful. CBLB502, a toll-like receptor 5 (TLR5) agonist derived from Salmonella flagellin, exhibits anticancer and radioprotective activities via modulation of TLRs and the nuclear factor kappa B (NF-κB) signaling pathway and can protect against acute renal ischemic failure. In this study, we intend to examine the effects of CBLB502 on both TLR responses and the interleukin (IL) and NF-κB signaling pathways in UC treatment.Methods: The UC mouse model was prepared in BALB/c mice by administering 2,4,6-trinitrobenzene sulfonic acid (TNBS). CBLB502 was used as the therapeutic drug. After CBLB502 therapy, the IL and tumor necrosis factor-α (TNF-α) levels were measured by ELISA. Total RNA and protein of colon samples was extracted.Results: We found that CBLB502 had a distinctive therapeutic effect in the UC model. In control group animals, IL-10 expression in serum was 91.48±24.38 ng/mL; this was higher than in the model group (59.36±14.46 ng/mL, P<0.05) or the treatment group (54.29±5.83 ng/mL, P<0.05). In model group animals, the concentration of TNF-α in serum was 140.11±12.70 ng/mL, which was lower than protein levels in the control group (173.86±29.26 ng/mL, P<0.05). The mRNA levels of TLR1,2,3,4,6,7,8, and 9 in the CBLB502 treatment group were significantly lower than in the model group (P<0.05). Western blot revealed that CBLB502 also reduced NF-κB expression in the mouse colon, but that NF-κB expression was not significantly lower than the model group.Conclusions: CBLB502 can reduce mucosal damage induced by TNBS and inhibit inflammation and TLR expression. The inhibition of UC by CBLB502 is strictly TLR-IL-dependent and is dose-dependent within the efficacious dose range. Therefore, our results suggested that CBLB502 might be a candidate drug for the treatment of UC.

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Section: Introductionmentioning

confidence: 88%

“…CBLB502 exerts radioprotective activities and inhibits acute renal ischemic failure (8)(9)(10)12). In this study, we examined the treatment of UC using CBLB502 via the effects of CBLB502 on TLR responses and IL and NF-κB signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation

Xu¹,

Dong

et al. 2016

Ann. Transl. Med.

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“…TLR5 agonistic agent CBLB502 was obtained from Cleveland BioLabs, Inc. (8,55), and LPS from Escherichia coli 055:B5 was purchased from Sigma. Purified hamster anti-mouse Fas Ab, clone Jo2, was purchased from BD Biosciences.…”

Section: Methodsmentioning

confidence: 99%

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

Burdelya

Brackett

Kojouharov

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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111

175

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Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.breast cancer | colon cancer | neutrophils | natural killer cells | Salmonella T oll-like receptors (TLRs) recognize and are activated by specific patterns in molecules that are produced by a broad range of microbial pathogens but are not present in host molecules. Activation of TLRs by these pathogen-associated molecular patterns leads to induction of infection-fighting innate immune responses (1). Various TLR agonists have been considered for multiple clinical applications, including cancer immunotherapy (2-4), and one, the TLR7 agonist imiquimod, is approved for topical treatment of basal cell carcinoma (5).Although signaling pathways induced by different TLRs all result in mobilization of an innate immune response and involve activation of nuclear factor kappa B (NF-κB), the key regulator of immunity (6, 7), TLR5 is a particularly attractive candidate for therapeutic targeting for several reasons. First, bacterial flagellin, the natural ligand of TLR5, was found to have strong radioprotective effects in rodents and nonhuman primates (8). CBLB502 is a rationally designed derivative of Salmon...

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“…35 Serum IL6 is also required for efficient radioprotection of CBLB502, a TLR5-agonist that protects mice from lethal doses of GR. 36 Thus, it is plausible that IL6 mediates some part of the radioprotective effect of the AOX diet in hematopoietic cells. IL6 is also expressed in cancer cells following exposure to GR and promotes resistance to radiochemotherapy.…”

Section: Resultsmentioning

confidence: 99%

The effects of antioxidants on gene expression following gamma-radiation (GR) and proton radiation (PR) in mice in vivo

et al. 2013

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Identification of Granulocyte Colony-Stimulating Factor and Interleukin-6 as Candidate Biomarkers of CBLB502 Efficacy as a Medical Radiation Countermeasure

Cited by 99 publications

References 45 publications

CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation

CBLB502 administration protects gut mucosal tissue in ulcerative colitis by inhibiting inflammation

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist

The effects of antioxidants on gene expression following gamma-radiation (GR) and proton radiation (PR) in mice in vivo

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