title: Arsenic trioxide induces apoptosis of human monocytes during macrophagic differentiation through nuclear factor-kappaB-related survival pathway down-regulation.
abstract: Arsenic trioxide (As(2)O(3)) is known to be toxic toward leukemia cells. In this study, we determined its effects on survival of human monocytic cells during macrophagic differentiation, an important biological process involved in the immune response. As(2)O(3) used at clinically relevant pharmacological concentrations induced marked apoptosis of human blood monocytes during differentiation with either granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor. Apoptosis of monocytes was associated with increased caspase activities and decreased DNA binding of p65 nuclear factor-kappaB (NF-kappaB); like As(2)O(3), the selective NF-kappaB inhibitor (E)-3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (Bay 11-7082) strongly reduced survival of differentiating monocytes. The role of NF-kappaB in arsenic toxicity was also studied in promonocytic U937 cells during phorbol 12-myristate 13-acetate-induced macrophagic differentiation. In these cells, As(2)O(3) first reduced DNA binding of p65 NF-kappaB and subsequently induced apoptosis. In addition, overexpression of the p65 NF-kappaB subunit, following stable infection with a p65 retroviral expressing vector, increased survival of As(2)O(3)-treated U937 cells. As(2)O(3) specifically decreased protein levels of X-linked inhibitor of apoptosis protein and FLICE-inhibitory protein, two NF-kappaB-regulated genes in both U937 cells and blood monocytes during their differentiations. Finally, As(2)O(3) was found to inhibit macrophagic differentiation of monocytic cells when used at cytotoxic concentrations; however, overexpression of the p65 NF-kappaB subunit in U937 cells reduced its effects toward differentiation. In contrast to monocytes, well differentiated macrophages were resistant to low concentrations of As(2)O(3). Altogether, our study demonstrates that clinically relevant concentrations of As(2)O(3) induced marked apoptosis of monocytic cells during in vitro macrophagic differentiation likely through inhibition of NF-kappaB-related survival pathways.
authors.affiliation: Unité INSERM U620, Dé-toxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, 2 avenue du Pr. Léon Bernard, 35043 Rennes, France.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lemarie
authors.forename: Claudie
authors.initials: C
authors.lastname: Morzadec
authors.forename: Delphine
authors.initials: D
authors.lastname: Mérino
authors.forename: Olivier
authors.initials: O
authors.lastname: Micheau
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
authors.forename: Laurent
authors.initials: L
authors.lastname: Vernhet
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001562:Benzimidazoles; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D005456:Fluorescent Dyes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects*; D016328:NF-kappa B / Q000502:physiology*; D016759:Oncogene Protein p65(gag-jun) / Q000096:biosynthesis / Q000235:genetics; D010087:Oxides / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020298:U937 Cells; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D001562:Benzimidazoles; D002273:Carcinogens; D005456:Fluorescent Dyes; D016328:NF-kappa B; D016759:Oncogene Protein p65(gag-jun); D010087:Oxides; D051636:X-Linked Inhibitor of Apoptosis Protein; D012313:RNA; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate; C017807:bisbenzimide ethoxide trihydrochloride; D000077237:Arsenic Trioxide