Involvement of immune-related factors in diclofenac-induced acute liver injury in mice

Yano, Azusa; Higuchi, Satonori; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1016/j.tox.2012.01.008

Cited by 62 publications

(67 citation statements)

References 41 publications

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“…We have assessed COX1 and COX2 activity by ELISA but found the basal COX activity in the melanoma lines too low to robustly assess inhibition with NSAIDs (data not shown). Using qPCR we did see COX1 mRNA increase (2x) in VMM39 cells and IL-1beta mRNA increase (5x) in DM331 cells with diclofenac consistent with inhibition of COX activity (data not shown) (38,39). However, we found only a small number of gene expression changes to occur following diclofenac treatment for 8 hours and no changes consistent across both cell lines (Figure 6).…”

Section: Discussionmentioning

confidence: 65%

Synthetic Lethal Screening with Small-Molecule Inhibitors Provides a Pathway to Rational Combination Therapies for Melanoma

Roller

Axelrod

Capaldo

et al. 2012

Molecular Cancer Therapeutics

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Recent data demonstrate that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways suggesting why inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biological outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we performed a functional chemical genetic screen to identify novel interactions between signaling inhibitors that would not be predicted based on our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. The synergistic cytotoxicities identified did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. Among the most robust results was synergy between sorafenib, a multi-kinase inhibitor with activity against RAF, and diclofenac, a non-steroidal anti-inflammatory drug (NSAID). Drug substitution experiments using the NSAIDs celecoxib and ibuprofen or the MEK inhibitor PD325901 and the RAF inhibitor RAF265 suggest that inhibition of cyclooxygenase (COX) and MAP kinase signaling are targets for the synergistic cytotoxicity of sorafenib and diclofenac. Co-treatment with sorafenib and diclofenac interrupts a positive feedback signaling loop involving ERK, cPLA2, and COX. Genome-wide expression profiling demonstrates synergy-specific down-regulation of survival-related genes. This study has uncovered novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially depending on unexplored components of the cell genotype.

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Section: Discussionmentioning

confidence: 65%

Synthetic Lethal Screening with Small-Molecule Inhibitors Provides a Pathway to Rational Combination Therapies for Melanoma

Roller

Axelrod

Capaldo

et al. 2012

Molecular Cancer Therapeutics

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“…IL-17 has been detected in the sera from patients with idiosyncratic liver injury [48]. However, animal studies demonstrate elevations in IL-17 in early time points following large doses of acetaminophen [49] or diclofenac [50]. This surprising finding could suggest sustained induction of IL-17 in this disease process: early in the initiation of the immune response in addition to during the effector period.…”

Section: Immune Basis Of Drug Hepatotoxicitymentioning

confidence: 99%

Drug-Induced Hepatotoxicity: Metabolic, Genetic and Immunological Basis

Njoku

2014

IJMS

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Drug-induced hepatotoxicity is a significant cause of acute liver failure and is usually the primary reason that therapeutic drugs are removed from the commercial market. Multiple mechanisms can culminate in drug hepatotoxicity. Metabolism, genetics and immunology separately and in concert play distinct and overlapping roles in this process. This review will cover papers we feel have addressed these mechanisms of drug-induced hepatotoxicity in adults following the consumption of commonly used medications. The aim is to generate discussion around “trigger point” papers where the investigators generated new science or provided additional contribution to existing science. Hopefully these discussions will assist in uncovering key areas that need further attention.

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“…Reactive oxygen species are reduced to other forms of oxygen by mitochondria; this process may be deficient innonhealthyliver or when the liver is exposed to an extraordinary unwanted burden of toxins ( 3 - 6 ). This oxidant damage would disturb many parts of the cell structure in hepatocytes.…”

Section: Contextmentioning

confidence: 99%

“…This oxidant damage would disturb many parts of the cell structure in hepatocytes. Apoptosis (and not necrosis) is the main mechanism of liver injury, especially after drug related -including anesthetics- or viral injuries ( 6 - 14 ) at times ending in massive apoptosis ( 10 ). Apoptosis (programmed cell death) could be induced in two ways: intrinsic and extrinsic ( 9 , 11 ).…”

Section: Contextmentioning

confidence: 99%

The Role of Anesthetic Drugs in Liver Apoptosis

Dabbagh

Rajaei

2013

Hepat Mon

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ContextThe modern practice of anesthesia is highly dependent ona group of anesthetic drugs which many of them are metabolized in the liver.Evidence AcquisitionThe liver, of course, usually tolerates this burden. However, this is not always an unbroken rule. Anesthetic induced apoptosis has gained great concern during the last years; especially considering the neurologic system.ResultsHowever, we have evidence that there is some concern regarding their effects on the liver cells. Fortunately not all the anesthetics are blamed and even some could be used safely, based on the available evidence.ConclusionsBesides, there are some novel agents, yet under research, which could affect the future of anesthetic agents' fate regarding their hepatic effects.

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Involvement of immune-related factors in diclofenac-induced acute liver injury in mice

Cited by 62 publications

References 41 publications

Synthetic Lethal Screening with Small-Molecule Inhibitors Provides a Pathway to Rational Combination Therapies for Melanoma

Synthetic Lethal Screening with Small-Molecule Inhibitors Provides a Pathway to Rational Combination Therapies for Melanoma

Drug-Induced Hepatotoxicity: Metabolic, Genetic and Immunological Basis

The Role of Anesthetic Drugs in Liver Apoptosis

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