Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist (original) (raw)
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Cell Death & Disease
The toll-like receptor 5 (TLR5) agonist, CBLB502/Entolimod, is a peptide derived from bacterial flagellin and has been shown to protect against radiation-induced tissue damage in animal models. Here we investigated the protective mechanism of CBLB502 in the liver using models of ischemia-reperfusion injury and concanavalin A (ConA) induced immuno-hepatitis. We report that pretreatment of mice with CBLB502 provoked a concomitant activation of NF-κB and STAT3 signaling in the liver and reduced hepatic damage in both models. To understand the underlying mechanism, we screened for cytokines in the serum of CBLB502 treated animals and detected high levels of IL-22. There was no transcriptional upregulation of IL-22 in the liver, rather it was found in extrahepatic tissues, mainly the colon, mesenteric lymph nodes (MLN), and spleen. RNA-seq analysis on isolated hepatocytes demonstrated that the concomitant activation of NF-κB signaling by CBLB502 and STAT3 signaling by IL-22 produced a sy...
Gastroenterology, 2008
Background & Aims-Toll-like receptor (TLR)-dependent signaling pathways have been proposed as immunotherapeutic targets against invading pathogens and tumorigenesis. Here we investigated whether TLR5-dependent signaling modulates colonic tumor development in a mouse xenograft model of human colon cancer. Methods-The expression of MyD88 or TLR5 was stably knocked down in human colon cancer cells (DLD-1). Nude mice were subcutaneously implanted with MyD88-KD, TLR5-KD, or control cells (n=16) to examine the pathophysiology of tumor xenografts. Protein micro-array assessed the differential expression of cytokines in these tumors. Leukocyte infiltration and tumor angiogenesis were assessed by immunohistochemistry with antibodies against neutrophil (Gr-1, 7/4) or macrophage specific antigens (CD68, F4-80), and the vascular endothelial cell marker PECAM-1/ CD31, respectively. Tumor xenografts from DLD-1 cells were treated with flagellin (5.0 µg/kg, one injection/every 2 days for 3 weeks) and tumor regression and histopathology of these tumors were examined. Results-Lack of MyD88 or TLR5 expression dramatically enhanced tumor growth and inhibited tumor necrosis in mouse xenograft of human colon cancer. In contrast, TLR5 activation by peritumoral flagellin treatment substantially increased tumor necrosis, leading to significant tumor regression. Tumors from MyD88-or TLR5-KD cells revealed the reduced production of neutrophil attracting chemokines (ENA-78, MIP3α, and IL-8). Consequently, neutrophil infiltration was dramatically diminished in MyD88 or TLR5 deficient tumor xenografts, while tumor-associated macrophage infiltration or angiogenesis was not changed. Conclusions-TLR5 engagement by flagellin mediates innate immunity and elicits potent antitumor activity, indicating that TLR5-dependent signaling could be a potential immunotherapeutic target to modulate colonic tumors.
An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models
Science, 2008
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–κB 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 biologic...
TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects
PLOS ONE
Tumor necrosis factor alpha (TNF) is capable of inducing regression of solid tumors. However, TNF released in response to Toll-like receptor 4 (TLR4) activation by bacterial lipopolysaccharide (LPS) is the key mediator of cytokine storm and septic shock that can cause severe tissue damage limiting anticancer applications of this cytokine. In our previous studies, we demonstrated that activation of another Toll-like receptor, TLR5, could protect from tissue damage caused by a variety of stresses including radiation, chemotherapy, Fas-activating antibody and ischemia-reperfusion. In this study, we tested whether entolimod could counteract TNF-induced toxicity in mouse models. We found that entolimod pretreatment effectively protects livers and lungs from LPS-and TNF-induced toxicity and prevents mortality caused by combining either of these agents with the sensitizer, D-galactosamine. While LPS and TNF induced significant activation of apoptotic caspase 3/7, lipid tissue peroxidation and serum ALT accumulation in mice without entolimod treatment, these indicators of toxicity were reduced by entolimod pretreatment to the levels of untreated control mice. Entolimod was effective when injected 0.5-48 hours prior to, but not when injected simultaneously or after LPS or TNF. Using chimeric mice with hematopoiesis differing in its TLR5 status from the rest of tissues, we showed that this protective activity was dependent on TLR5 expression by non-hematopoietic cells. Gene expression analysis identified multiple genes upregulated by entolimod in the liver and cultured hepatocytes as possible mediators of its protective activity. Entolimod did not interfere with the antitumor activity of TNF in mouse hepatocellular and colorectal tumor models. These results support further development of TLR5 agonists to increase tissue resistance to cytotoxic cytokines, reduce the risk of septic shock and enable safe systemic application of TNF as an anticancer therapy.
Oncotarget, 2014
Myelosuppression and gastrointestinal damage are common side effects of cancer treatment limiting efficacy of DNA-damaging chemotherapeutic drugs. The Toll-like receptor 5 (TLR5) agonist Entolimod has demonstrated efficacy in mitigating damage to hematopoietic and gastrointestinal tissues caused by radiation. Here, using 5-Fluorouracil (5-FU) treated mice as a model of chemotherapy-induced side effects, we demonstrated significant reduction in the severity of 5-FU-induced morbidity and increased survival accompanied by the improved integrity of intestinal tissue and stimulated the restoration of hematopoiesis. Entolimod-stimulated IL-6 production was essential for Entolimod's ability to rescue mice from death caused by doses of 5-FU associated with hematopoietic failure. In contrast, IL-6 induction was not necessary for protection and restoration of drug-damaged gastrointestinal tissue by Entolimod. In a syngeneic mouse CT26 colon adenocarcinoma model, Entolimod reduced the syst...
Hepatology, 2011
I can hardly share the passionate enthusiasm of Breuhahn et al. for the ''dramatic'' improvements in understanding of molecular pathogenesis of hepatocellular carcinoma (HCC) and the claim for ''further rationally designed clinical trials based on molecular evidence''. 1 Among the causes of HCC, they cite aflatoxins and hemochromatosis but failed, as too many do, to cite tobacco, which represents the cause of one-third of the cases. 2 Despite the success of the hepatitis B vaccine and the cure for hepatitis C, HCC remains a growing epidemic due to alcohol, tobacco, and processed foods (obesity and diabetes). 3 Here are the three agents of the modern epidemics. Considering ''molecular evidence'', a PubMed search for ''geneexpression profiling'' and ''cancer'' provides more than 17,000 references since 1999. However, out of hundreds of biomarkers, KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is the only one integrated into clinical practice. It is limited to metastatic colorectal cancer, which constitutes half of all patients with colorectal cancer. Evidence was obtained in 2008 from a post hoc analysis of the CRYSTAL trial (study EMR 62202-013) with cetuximab, and the first trial designed with an intention-to-treat analysis, PRIME (study 20050203), has just been published. 4 The effect, although statistically significant, has very limited relevance: in wild-type KRAS, panitumumab-FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) increases progression-free survival by 1.6 months compared with FOLFOX4 alone. Medicine must avoid ''sciensationalism'' (sensationalism in science). 5 If more research is needed, it must be concerned with how to improve the implementation of evidence-based care and public policies against the leading avoidable causes of cancer worldwide: tobacco, alcohol, and obesity. A focus on molecular biology that ignores medical practice, interventional epidemiology, and social and political sciences will improve neither patient care nor prevention.
Hepatology, 2010
Increasing evidence suggests that the presence of endotoxemia is of substantial clinical relevance to patients with cirrhosis, but it is unclear whether and how gut-derived LPS amplifies the tumorigenic response of the liver. We found that the circulating levels of LPS were elevated in animal models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor Toll-like receptor 4 (TLR4) in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-jB activation and sensitizing the liver to reactive oxygen species (ROS)-induced toxicity, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored diethylnitrosamine (DEN)induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. Meanwhile, deletion of gut-derived endotoxin suppressed DENinduced cytokine production and compensatory proliferation, whereas in vivo LPS prechallenge promotes hepatocyte proliferation. Conclusion: Our data indicate that sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in patients with cirrhosis who are at risk of developing HCC.
Cancers
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise...