title: H89 enhances the sensitivity of cancer cells to glyceryl trinitrate through a purinergic receptor-dependent pathway.
abstract: High doses of the organic nitrate glyceryl trinitrate (GTN), a nitric oxide (NO) donor, are known to trigger apoptosis in human cancer cells. Here, we show that such a cytotoxic effect can be obtained with subtoxic concentrations of GTN when combined with H89, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide.2HCl. This synergistic effect requires the generation of reactive oxygen species (ROS) from H89 and NO from GTN treatment that causes cGMP production and PKG activation. Furthermore, the GTN/H89 synergy was attenuated by inhibition of P2-purinergic receptors with suramin and competition with ATP/UDP. By down-regulating genes with antisense oligonucleotides, P2-purinergic receptors P2X3, P2Y1, and P2Y6 were found to have a role in creating this cytotoxic effect. Thus, H89 likely acts as an ATP mimetic synergizing with GTN to trigger apoptosis in aggressive cancer cells.
authors.affiliation: EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon, F-21000, France.|Inserm U866, Dijon, F-21000, France.|EA7269, University of Burgundy, Dijon, F-21000, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Cortier
authors.affiliation: EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon, F-21000, France.|Inserm U866, Dijon, F-21000, France.|EA7269, University of Burgundy, Dijon, F-21000, France.
authors.forename: Rahamata
authors.initials: R
authors.lastname: Boina-Ali
authors.affiliation: EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon, F-21000, France.|Inserm U866, Dijon, F-21000, France.|EA7269, University of Burgundy, Dijon, F-21000, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Racoeur
authors.affiliation: EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon, F-21000, France.|Inserm U866, Dijon, F-21000, France.|EA7269, University of Burgundy, Dijon, F-21000, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Paul
authors.affiliation: Inserm U866, Dijon, F-21000, France.|Inserm UMR1009, Gustave Roussy Institute, Villejuif F-94805, France.|University Paris-Sud, Faculty of Medicine, Le Kremlin-Bicêtre, F-94800, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon, F-21000, France.|Inserm U866, Dijon, F-21000, France.|EA7269, University of Burgundy, Dijon, F-21000, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Jeannin
authors.affiliation: EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon, F-21000, France.|Inserm U866, Dijon, F-21000, France.|EA7269, University of Burgundy, Dijon, F-21000, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Bettaieb
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004357:Drug Synergism; D020869:Gene Expression Profiling; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry*; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D009369:Neoplasms / Q000378:metabolism*; D009569:Nitric Oxide / Q000737:chemistry; D005996:Nitroglycerin / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry; D011983:Receptors, Purinergic / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000737:chemistry*; D014162:Transfection
chemical_list: D007546:Isoquinolines; D016376:Oligonucleotides, Antisense; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D011983:Receptors, Purinergic; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D058472:Receptors, Purinergic P2Y1; D013449:Sulfonamides; C099845:purinoceptor P2Y6; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D005996:Nitroglycerin; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: GTN; H89; cGMP; cancer; purinergic receptors