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.
Subject(s)
Colonic Neoplasms/pathology , Isoquinolines/chemistry , Neoplasms/metabolism , Nitroglycerin/chemistry , Receptors, Purinergic/metabolism , Sulfonamides/chemistry , Adenosine Triphosphate/chemistry , Animals , Apoptosis , Cell Line, Tumor , Colonic Neoplasms/metabolism , Drug Synergism , Gene Expression Profiling , Humans , Membrane Potential, Mitochondrial , Mice , Nitric Oxide/chemistry , Oligonucleotides, Antisense/chemistry , Protein Kinase Inhibitors/chemistry , Reactive Oxygen Species/chemistry , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2X3/metabolism , Receptors, Purinergic P2Y1/metabolism , Signal Transduction , TransfectionABSTRACT
Previous studies have shown that maintaining high hemoglobin levels in patients after chemotherapy reduced the length of neutropenia. Thus, we undertook a randomized, controlled, clinical trial in children undergoing allogeneic bone marrow transplantation after receiving a myeloablative conditioning regimen to compare 2 hemoglobin thresholds as triggers for red blood cell transfusion: 120 g/L in the experimental arm and 70 g/L in the control arm. The Data and Safety Monitoring Board closed the study after enrollment of the sixth patient because 3 patients in the experimental arm contracted veno-occlusive disease, but none in the control arm did (P = .05). Ascites was present in all 3 patients, pleura effusion in 2, and portal vein thrombosis in 2. One patient experienced hepatic failure and required treatment with the molecular adsorbent recycling system. Another patient required hemodialysis for renal failure. No major imbalance between groups was seen with regard to risk factors for veno-occlusive disease. Therefore, maintaining the hemoglobin at higher levels should be avoided after hematopoietic stem cell transplantation.
Subject(s)
Bone Marrow Transplantation/adverse effects , Erythrocyte Transfusion , Hemoglobins/analysis , Hepatic Veno-Occlusive Disease/etiology , Transplantation Conditioning , Adolescent , Ascites/etiology , Ascites/pathology , Child , Female , Hepatic Veno-Occlusive Disease/pathology , Humans , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/therapy , Male , Myeloablative Agonists/therapeutic use , Myelodysplastic Syndromes/immunology , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/therapy , Pleural Effusion/etiology , Pleural Effusion/pathology , Risk Factors , Thrombosis/etiology , Thrombosis/pathology , Transplantation, HomologousABSTRACT
This report summarizes the present state of our knowledge pertaining to the NO-induced resistance or sensitization of tumor cell death. The effects of NO and its synergy with members of the TNF family, with cytotoxic drugs, and with ionizing radiations have been investigated. The dual effect of NO-induced resistance or sensitization and the underlying molecular mechanisms are discussed.
