H89 enhances the sensitivity of cancer cells to glyceryl trinitrate through a purinergic receptor-dependent pathway
Metrics: PDF 1836 views | HTML 2072 views | ?
Marion Cortier1,2,3, Rahamata Boina-Ali1,2,3, Cindy Racoeur1,2,3, Catherine Paul1,2,3, Eric Solary2,4,5, Jean-François Jeannin1,2,3, Ali Bettaieb1,2,3
1EPHE, Tumor Immunology and Immunotherapy Laboratory, Dijon, F-21000, France
2Inserm U866, Dijon, F-21000, France
3EA7269, University of Burgundy, Dijon, F-21000, France
4Inserm UMR1009, Gustave Roussy Institute, Villejuif F-94805, France
5University Paris-Sud, Faculty of Medicine, Le Kremlin-Bicêtre, F-94800, France
Ali Bettaieb, e-mail: email@example.com
Keywords: H89, GTN, cancer, purinergic receptors, cGMP
Received: October 08, 2014 Accepted: January 09, 2015 Published: February 04, 2015
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.