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Effects of Combined Admistration of Imatinib and Sorafenib in a Murine Model of Liver Fibrosis.

Abstract
Liver fibrosis is defined as excessive extracellular matrix deposition in the hepatic parenchyma as a consequence of complex interactions among matrix-producing hepatic stellate cells (HSCs) and liver-resident and infiltrating cells. In addition to the liver, the process of fibrosis may represent end-stage disease of several diseases including kidneys, lungs, spleens, heart, muscles and at certain extent, the central nervous system and the peripheral nerves. To date, antifibrotic treatment of fibrosis represents an unconquered area for drug development. The aim of the present study was to test the efficacy of a new drug combination for the treatment of hepatic fibrosis in order to provide a proof-of-concept for the use of therapeutic agents in clinical practice. For this purpose, we have studied the effects of the PDGF inhibitor imatinib and the angiogenesis inhibitor sorafenib, administered alone or in combination, in reducing the progression of the fibrogenetic process in a pre-clinical model of liver damage induced in mice by repeated administration of Concanavalin A (ConA), resembling long-tern autoimmune hepatitis. Our results suggest that treatments with imatinib and sorafenib can modulate potently and, in a superimposable fashion, the fibrinogenic process when administered alone. However, and in agreement with the computational data presently generated, they only exert partial overlapping antifibrotic effects in modulating the main pathways involved in the process of liver fibrosis, without significant additive or synergist effects, when administered in combination.
AuthorsAntonio Pesce, Rosella Ciurleo, Alessia Bramanti, Eliana Concetta Armeli Iapichino, Maria Cristina Petralia, Gaetano Giuseppe Magro, Paolo Fagone, Placido Bramanti, Ferdinando Nicoletti, Katia Mangano
JournalMolecules (Basel, Switzerland) (Molecules) Vol. 25 Issue 18 (Sep 20 2020) ISSN: 1420-3049 [Electronic] Switzerland
PMID32962198 (Publication Type: Journal Article)
Chemical References
  • Angiogenesis Inhibitors
  • Protein Kinase Inhibitors
  • Concanavalin A
  • Imatinib Mesylate
  • Sorafenib
  • Receptors, Platelet-Derived Growth Factor
Topics
  • Angiogenesis Inhibitors (pharmacology)
  • Animals
  • Computer Simulation
  • Concanavalin A (metabolism)
  • Disease Models, Animal
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Hepatic Stellate Cells
  • Humans
  • Imatinib Mesylate (pharmacology)
  • Liver (drug effects)
  • Liver Cirrhosis (chemically induced, drug therapy)
  • Mice
  • Mice, Inbred BALB C
  • Protein Kinase Inhibitors (pharmacology)
  • Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors)
  • Sorafenib (pharmacology)

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