title: Nonsteroidal anti-inflammatory drugs modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways.
abstract: In this report, selected non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin and nimesulide, and analgesics acetaminophen, alone, as well as in combination with isoflavone genistein as potential glycosaminoglycan (GAG) metabolism modulators were considered for the treatment of mucopolysaccharidoses (MPSs) with neurological symptoms due to the effective blood-brain barrier (BBB) penetration properties of these compounds. We found that indomethacin and nimesulide, but not acetaminophen, inhibited GAG synthesis in fibroblasts significantly, while the most pronounced impairment of glycosaminoglycan production was observed after exposure to the mixture of nimesulide and genistein. Phosphorylation of the EGF receptor (EGFR) was inhibited even more effective in the presence of indomethacin and nimesulide than in the presence of genistein. When examined the activity of phosphatidylinositol-3-kinase (PI3K) production, we observed its most significant decrease in the case of fibroblast exposition to nimesulide, and afterwards to indomethacin and genistein mix, rather than indomethacin used alone. Some effects on expression of individual GAG metabolism-related and lysosomal function genes, and significant activity modulation of a number of genes involved in intracellular signal transduction pathways and metabolism of DNA and proteins were detected. This study documents that NSAIDs, and their mixtures with genistein modulate cellular glycosaminoglycan synthesis by affecting EGFR and PI3K signaling pathways.
authors.affiliation: Department of Molecular Biology and Genetics, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Mozolewski
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Laboratory of Molecular Biology (affiliated with the University of Gdańsk), Wita Stwosza 59, 80-308 Gdańsk, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Moskot
authors.affiliation: Department of Molecular Biology and Genetics, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jakóbkiewicz-Banecka
authors.affiliation: Department of Molecular Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Węgrzyn
authors.affiliation: Department of Molecular Biology and Genetics, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Bocheńska
authors.affiliation: Department of Molecular and Cellular Biology, Intercollegiate Faculty of Biotechnology UG-MUG, Abrahama 58, 80-307 Gdańsk, Poland.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Banecki
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Laboratory of Molecular Biology (affiliated with the University of Gdańsk), Wita Stwosza 59, 80-308 Gdańsk, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gabig-Cimińska
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D006025:Glycosaminoglycans; D058539:Phosphatidylinositol 3-Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors