Molecular Mechanisms of Hepatocellular Apoptosis Induced by Trovafloxacin-Tumor Necrosis Factor-alpha Interaction

Beggs, Kevin M.; Fullerton, Aaron; Miyakawa, Kazuhisa; Ganey, Patricia E.; Roth, Robert A.

doi:10.1093/toxsci/kft226

Cited by 30 publications

(48 citation statements)

References 40 publications

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“…56 Another study also showed that TNF treatment could cause apoptosis and DNA damage in HepG2 cells. 57 In addition, we found a significant overlap between up-regulated proteincoding genes in prostate cancer and down-regulated genes after lnc-SNURF-1 knockdown (Fig. 7E, P = 0.0267), and a marginal significance between down-regulated protein-coding genes in prostate cancer and up-regulated genes in the knockdown data ( Fig.…”

Section: Systematic Evaluation Of Predicted Cancer-related Lncrnasmentioning

confidence: 73%

Identification of cancer-related lncRNAs through integrating genome, regulome and transcriptome features

Zhao

Liu

et al. 2015

Mol. BioSyst.

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LncRNAs have become rising stars in biology and medicine, due to their versatile functions in a wide range of important biological processes and active roles in various human cancers. Here, we developed a computational method based on the naïve Bayesian classifier method to identify cancer-related lncRNAs by integrating genome, regulome and transcriptome data, and identified 707 potential cancer-related lncRNAs. We demonstrated the performance of the method by ten-fold cross-validation, and found that integration of multi-omic data was necessary to identify cancer-related lncRNAs. We identified 707 potential cancer-related lncRNAs and our results showed that these lncRNAs tend to exhibit significant differential expression and differential DNA methylation in multiple cancer types, and prognosis effects in prostate cancer. We also found that these lncRNAs were more likely to be direct targets of TP53 family members than others. Moreover, based on 147 lncRNA knockdown data in mice, we validated that four of six mouse orthologous lncRNAs were significantly involved in many cancer-related processes, such as cell differentiation and the Wnt signaling pathway. Notably, one lncRNA, lnc-SNURF-1, which was found to be associated with TNF-mediated signaling pathways, was up-regulated in prostate cancer and the protein-coding genes affected by knockdown of the lncRNA were also significantly aberrant in prostate cancer patients, suggesting its probable importance in tumorigenesis. Taken together, our method underlines the power of integrating multi-omic data to uncover cancer-related lncRNAs.

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Section: Systematic Evaluation Of Predicted Cancer-related Lncrnasmentioning

confidence: 73%

Identification of cancer-related lncRNAs through integrating genome, regulome and transcriptome features

Zhao

Liu

et al. 2015

Mol. BioSyst.

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“…Toxicity was preceded by an increase and prolongation of TNF in the plasma of CPZ-LPS or CPZ-lipoteichoic acid coexposed animals, raising the possibility of a link between prolonged plasma TNF and hepatotoxicity, similar to what is observed during TVX-LPS coexposure. Another recent study described JNK-dependent cytotoxicity resulting from TVX/TNF coexposure in a hepatocyte cell line (Beggs et al, 2014). Therefore, it is possible that a common upstream stimulus in hepatocytes and macrophages activates JNK in response to TVX, and that this results in cell death in hepatocytes and increased cytokine release in macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…JNK has been implicated in cell-death signaling, and examples of JNK dependence in drug-inflammation interaction models of hepatocellular injury have been described (Gandhi et al, 2013;Beggs et al, 2014). Chlorpromazine (CPZ) is a phenothiazine antipsychotic drug associated with IDILI in humans, and coexposure of rats to CPZ and LPS precipitates liver injury (Buchweitz et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Trovafloxacin Potentiation of Lipopolysaccharide-Induced Tumor Necrosis Factor Release from RAW 264.7 Cells Requires Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase

Poulsen

Albee

Ganey

et al. 2014

J Pharmacol Exp Ther

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Trovafloxacin (TVX) is a fluoroquinolone antibiotic known to cause idiosyncratic, drug-induced liver injury (IDILI) in humans. The mechanism underlying this toxicity remains unknown. Previously, an animal model of IDILI in mice revealed that TVX synergizes with inflammatory stress from bacterial lipopolysaccharide (LPS) to produce a hepatotoxic interaction. The liver injury required prolongation of the appearance of tumor necrosis factor-a (TNF) in the plasma. The results presented here describe a model of TVX/LPS coexposure in RAW 264.7 cells acting as a surrogate for TNFreleasing cells in vivo. Pretreating cells with TVX for 2 hours before LPS addition led to increased TNF protein release into culture medium in a concentration-and time-dependent manner relative to cells treated with LPS or TVX alone. During the pretreatment period, TVX increased TNF mRNA, but this was less apparent when cells were exposed to TVX after LPS addition, suggesting that the pivotal signaling events that increase TNF expression occurred during the TVX pretreatment period. Indeed, TVX exposure increased activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase. Inhibition of either ERK or JNK decreased the TVX-mediated increase in TNF mRNA and LPS-induced TNF protein release, but p38 inhibition did not. These results demonstrated that the increased TNF appearance from TVX-LPS interaction in vivo can be reproduced in vitro and occurs in an ERK-and JNK-dependent manner.

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“…5 cytes can be used and many compounds can be assessed in a screening assay with small amounts of compound. It has been reported that idiosyncratic DILI is closely related to mitochondrial dysfunction (Wang, 2014;Dykens et al, 2008;Boelsterli and Lee, 2014) and apoptosis of the hepatocytes (Beggs et al, 2014). In the present study, in order to establish an in vitro assay for the estimation of the potential risk of the idiosyncratic DILI, we employed a combination assay of two endpoints, mitochondrial dysfunction and apoptosis, using cryopreserved human hepatocytes as a new approach.…”

Section: Discussionmentioning

confidence: 99%

“…Trovafloxacin, which causes idiosyncratic DILI, induces hepatocellular apoptosis in vitro when tumor necrosis factor-α (TNF-α) is co-treated. TNF-α activates caspase cascade and leads to apoptotic cell death (Beggs et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Usefulness of <i>in vitro</i> combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury

et al. 2016

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-Drug-induced liver injury (DILI) is one of the serious and frequent drug-related adverse events. This adverse event is a main reason for regulatory action pertaining to drugs, including restrictions in clinical indications and withdrawal from clinical trials or the marketplace. Idiosyncratic DILI especially has become a major clinical concern because of its unpredictable nature, frequent hospitalization, need for liver transplantation and high mortality. The estimation of the potential for compounds to induce idiosyncratic DILI is very difficult in non-clinical studies because the precise mechanism of idiosyncratic DILI is still unknown. Recently, many in vitro assays which indicate a possibility of the prediction of the idiosyncratic DILI have been reported. Among these, some in vitro assays focus on the effects of compounds on mitochondrial function and the apoptotic effects of compounds on human hepatocytes. In this study, we measured oxygen consumption rate (OCR) and caspase-3/7 activity as an endpoint of mitochondrial dysfunction and apoptosis, respectively, with human hepatocytes after treatment with compounds causing idiosyncratic DILI (troglitazone, leflunomide, ranitidine and diclofenac). Troglitazone and leflunomide decreased the OCR but did not affect caspase-3/7 activity. Ranitidine increased caspase-3/7 activity but did not affect the OCR. Diclofenac decreased the OCR and increased caspase-3/7 activity. Acetaminophen and ethanol, which are also hepatotoxicants but do not induce idiosyncratic DILI, did not affect the OCR or caspase-3/7 activity. These results indicate that a combination assay of mitochondrial dysfunction and apoptosis is useful for the estimation of potential risk of compounds to induce idiosyncratic DILI.

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Molecular Mechanisms of Hepatocellular Apoptosis Induced by Trovafloxacin-Tumor Necrosis Factor-alpha Interaction

Cited by 30 publications

References 40 publications

Identification of cancer-related lncRNAs through integrating genome, regulome and transcriptome features

Identification of cancer-related lncRNAs through integrating genome, regulome and transcriptome features

Trovafloxacin Potentiation of Lipopolysaccharide-Induced Tumor Necrosis Factor Release from RAW 264.7 Cells Requires Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase

Usefulness of <i>in vitro</i> combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury

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