Therapeutic potential of carfilzomib, an irreversible proteasome inhibitor, against acetaminophen-induced hepatotoxicity in mice

Alanazi, Abdulrazaq; Algfeley, Saleh G.; Alhosaini, Khaled; Korashy, Hesham M.; Imam, Faisal; Nagi, Mahmoud N.

doi:10.1002/jbt.21877

Cited by 4 publications

(2 citation statements)

References 39 publications

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“…As far as we know, this is the first report that CZM inhibits liver fibrosis in rodent models. Previously, intraperitoneal injection of CZM was reported to improve liver injury caused by acetaminophen overdose in a mouse model of liver injury 12 . However, based on the pharmacokinetics of CZM, the effect of intraperitoneal administration is unclear, and CZM should be considered for intravenous injection in mice.…”

Section: Discussionmentioning

confidence: 99%

Carfilzomib Shows Therapeutic Potential for Reduction of Liver Fibrosis by Targeting Hepatic Stellate Cell Activation

Fujiwara,

Takemura,

Tanaka

et al. 2024

Preprint

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Because hepatic stellate cells (HSCs) play a major role in fibrosis, we focused on HSCs as a potential target for the treatment of liver fibrosis. In this study, we attempted to identify drug candidates to inactivate HSCs and found that several proteasome inhibitors (PIs) reduced HSC viability. Our data showed that a second-generation PI, carfilzomib (CZM), suppressed the expression of fibrotic markers in primary murine HSCs at low concentrations of 5 or 10 nM. Since CZM was not toxic to HSCs up to a concentration of 12.5 nM, we examined its antifibrotic effects further. CZM achieved a clear reduction in liver fibrosis in the carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis without worsening of liver injury. Mechanistically, RNA sequence analysis of primary HSCs revealed that CZM inhibits mitosis in HSCs. In the CCl4-injured liver, amphiregulin, which is known to activate mitogenic signaling pathways and fibrogenic activity and is upregulated in murine and human metabolic dysfunction-associated steatohepatitis (MASH), was downregulated by CZM administration, leading to inhibition of mitosis in HSCs. Thus, CZM and next-generation PIs in development could be potential therapeutic agents for the treatment of liver fibrosis via inactivation of HSCs without liver injury.

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Section: Discussionmentioning

confidence: 99%

Carfilzomib Shows Therapeutic Potential for Reduction of Liver Fibrosis by Targeting Hepatic Stellate Cell Activation

Fujiwara,

Takemura,

Tanaka

et al. 2024

Preprint

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“…The effects of proteasome inhibition on drug-induced liver damage vary depending on the specific drugs used. Bortezomib and CFZ, but not MG132, show significant efficacy in mitigating acetaminopheninduced liver damage in animal models [16,17]. Proteasome inhibitors were shown to exert anti-inflammatory effects through different mechanisms [18].…”

Section: Introductionmentioning

confidence: 99%

Carfilzomib Mitigates Lipopolysaccharide/D-Galactosamine/Dimethylsulfoxide-Induced Acute Liver Failure in Mice

Alhareth,

Alanazi,

Alanazi

et al. 2023

Biomedicines

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Acute liver failure (ALF) is a disease accompanied by severe liver inflammation. No effective therapy is available yet apart from liver transplantation; therefore, developing novel treatments for ALF is urgently required. Inflammatory mediators released by NF-кB activation play an essential role in ALF. Proteasome inhibitors have many medical uses, such as reducing inflammation and NF-кB inhibition, which are believed to account for most of their repurposing effects. This study was undertaken to explore the possible protective effects and the underlying mechanisms of carfilzomib, a proteasome inhibitor, in a mouse model of ALF induced by lipopolysaccharide/D-galactosamine/dimethylsulfoxide (LPS/GalN/DMSO). Carfilzomib dose-dependently protected mice from LPS/GalN/DMSO-induced liver injury, as indicated by the decrease in serum alanine aminotransferase and aspartate aminotransferase levels. LPS/GalN/DMSO increased TNF-α, NF-кB, lipid peroxidation, NO, iNOS, cyclooxygenase-II, myeloperoxidase, and caspase-3 levels. Carfilzomib administration mitigated LPS/GalN/DMSO-induced liver damage by decreasing the elevated levels of TNF-α, NF-кB, lipid peroxidation, nitric oxide, iNOS, cyclooxygenase-II, myeloperoxidase, caspase-3, and histopathological changes. A restored glutathione level was also observed in the carfilzomib-treated LPS/GalN/DMSO mice. Our results demonstrate that carfilzomib protects against LPS/GalN/DMSO-induced ALF by inhibiting NF-кB, decreasing inflammatory mediators, oxidative/nitrosative stress, neutrophil recruitment, and apoptosis, suggesting that carfilzomib may be a potential therapeutic agent for ALF.

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Genetic Polymorphisms in Antioxidant Enzymes Modulate the Susceptibility of Idiosyncratic Antituberculous Drug‐Induced Liver Injury and Treatment Outcomes in Patients with Tuberculosis

et al. 2019

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BackgroundThe pathogenic mechanism of antituberculous drug‐induced liver injury (ATDILI) is associated with antioxidant enzymes. The objective of the present study was to investigate the associations of ATDILI susceptibility with genetic polymorphisms of antioxidant enzyme genes including nitric oxide synthase 2 (NOS2), thioredoxin reductase 1 (TXNRD1), superoxide dismutase 2 (SOD2), BTB domain and CNC homolog 1 (BACH1), and MAF bZIP transcription factor K (MAFK).MethodsThirty tag single nucleotide polymorphisms (tag‐SNPs) from the all candidate genes were genotyped in a 2‐stage cohort study including an initial discovery stage with 461 ATDILI patients and 466 controls and a replication stage with 216 ATDILI patients and 432 controls. The frequencies and distributions of genotypes and haplotypes were compared between the case and control groups. Three different genetic models including dominant, recessive, and additive models were used to determine the associations with susceptibility to ATDILI.ResultsThe SNPs rs9906835, rs944725, and rs3794764 of the NOS2 gene were significantly associated with an increased risk of ATDILI. The MAFK rs3735656 SNP was significantly associated with a decreased risk for ATDILI. The AAA haplotype of the NOS2 gene was associated with susceptibility to ATDILI. The treatment outcomes of patients with tuberculosis were further affected by genetic variants of the NOS2 and MAFK genes.ConclusionsGenetic polymorphisms of NOS2 and MAFK are associated with ATDILI susceptibility in Chinese patients with tuberculosis. The variants in NOS2 and MAFK affect treatment outcomes of tuberculosis patients. Further studies are needed to better understand the molecular mechanisms of ATDILI susceptibility via regulation of the expression of ATDILI‐susceptibility genes and proteins.

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Therapeutic potential of carfilzomib, an irreversible proteasome inhibitor, against acetaminophen-induced hepatotoxicity in mice

Cited by 4 publications

References 39 publications

Carfilzomib Shows Therapeutic Potential for Reduction of Liver Fibrosis by Targeting Hepatic Stellate Cell Activation

Carfilzomib Shows Therapeutic Potential for Reduction of Liver Fibrosis by Targeting Hepatic Stellate Cell Activation

Carfilzomib Mitigates Lipopolysaccharide/D-Galactosamine/Dimethylsulfoxide-Induced Acute Liver Failure in Mice

Genetic Polymorphisms in Antioxidant Enzymes Modulate the Susceptibility of Idiosyncratic Antituberculous Drug‐Induced Liver Injury and Treatment Outcomes in Patients with Tuberculosis

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