title: The novel c-Met inhibitor capmatinib mitigates diethylnitrosamine acute liver injury in mice.
abstract: The receptor tyrosine kinase mesenchymal-epithelial transition factor (c-Met) sits at the interface between controlled cellular division of organogenesis and uncontrolled cellular division of carcinogenesis. c-Met contribution to the initial phases of liver injury and inflammation is still not resolved. Herein, we investigated the selective pharmacological intervention of c-Met by capmatinib (formerly known as INC280) in the diethylnitrosamine (DEN) acute liver injury model in mice. c-Met inhibition by capmatinib reduced DEN-induced elevation of the pro-inflammatory cytokines TNF-α, IL-1β, IL-17A, IL-23(p19/40) and IFN-γ, which correlated well with serum markers of hepatocellular injury (ALT, AST and LDH). The protective effects possessed by capmatinib were mainly mediated by inhibiting inflammatory cells infiltration to the liver. However, hematoxylin-eosin and bax-immunohistochemical stainings revealed that capmatinib (at a dose of 10, but not 5mg/kg) aggravated DEN-induced hepatocellular ballooning and apoptosis, respectively. These effects were concordant with hepatocellular overexpression of the amino acid transporter CD98. Such capmatinib effects arised mostly from exaggerating the elevation of the mutagenic lipid peroxide 4-HNE along with MDA that enhanced DEN-induced compensatory proliferation evidenced by PCNA expression. In conclusion, inhibition of c-Met activation by capmatinib may provide protection against liver injury, but may trigger undesirable elevation of the mutagenic 4-HNE.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. Electronic address: mshaker2222@yahoo.com.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Shaker
authors.affiliation: Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: Ashamallah
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Mesery
mesh_terms: D000818:Animals; D001549:Benzamides; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D004052:Diethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D007093:Imidazoles; D014227:Triazines; D004052:Diethylnitrosamine; D019859:Proto-Oncogene Proteins c-met; C000613976:capmatinib
keywords: 4-Hydroxynonenal; C-Met; Capmatinib; Diethylnitrosamine