H89 enhances the sensitivity of cancer cells to glyceryl trinitrate through a purinergic receptor-dependent pathway

Marion Cortier; Rahamata Boina-Ali; Cindy Racoeur; Catherine Paul; Eric Solary; Jean-François Jeannin; Ali Bettaieb

doi:10.18632/oncotarget.3124

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Research Papers:

H89 enhances the sensitivity of cancer cells to glyceryl trinitrate through a purinergic receptor-dependent pathway

Marion Cortier _, Rahamata Boina-Ali, Cindy Racoeur, Catherine Paul, Eric Solary, Jean-François Jeannin and Ali Bettaieb

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Oncotarget. 2015; 6:6877-6886. https://doi.org/10.18632/oncotarget.3124

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Abstract

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

Correspondence to:

Ali Bettaieb, e-mail: [email protected]

Keywords: H89, GTN, cancer, purinergic receptors, cGMP

Received: October 08, 2014 Accepted: January 09, 2015 Published: February 04, 2015

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.

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Research Papers:

H89 enhances the sensitivity of cancer cells to glyceryl trinitrate through a purinergic receptor-dependent pathway

Abstract