Molecular mechanism of violacein-mediated human leukemia cell death

• Published in: Blood Vol. 104; no. 5; pp. 1459 - 1464
• Main Authors: Ferreira, Carmen Veríssima, Bos, Carina L., Versteeg, Henri H., Justo, Giselle Z., Durán, Nelson, Peppelenbosch, Maikel P.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-09-2004; The Americain Society of Hematology
• Subjects: Antigens, CD - metabolism; Biological and medical sciences; Caspase 3; Caspases - metabolism; Cell Death - drug effects; Cell Survival - drug effects; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - metabolism; DNA-Binding Proteins - metabolism; Hematologic and hematopoietic diseases; HL-60 Cells; Humans; Indoles - pharmacology; K562 Cells; Leukemia, Promyelocytic, Acute; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; NF-kappa B - metabolism; Phosphorylation; Receptors, Tumor Necrosis Factor - metabolism; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction - drug effects; STAT1 Transcription Factor; STAT2 Transcription Factor; Trans-Activators - metabolism; U937 Cells; Up-Regulation - drug effects; Antineoplastic agent; Human; Chromobacterium violaceum; Violacein; Leukemia; Cytotoxicity; Malignant hemopathy; Biological activity; HL60 cell line; Tumor necrosis factor receptor associated factor; Established cell line; Pigments; Bacteria; Indole derivatives; Mechanism of action; Apoptosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-02-0594

Violacein, a pigment isolated fromChromobacterium violaceumin the Amazon River, presents diverse biologic properties and attracts interest as a consequence of its antileukemic activity. Elucidation of the molecular mechanism mediating this activity will provide further relevant information for understanding its effects on the cellular physiology of untransformed cells and for considering its possible clinical application. Here, we show that violacein causes apoptosis in HL60 leukemic cells but is ineffective in this respect in other types of leukemia cells or in normal human lymphocytes and monocytes. Violacein cytotoxicity in HL60 cells was preceded by activation of caspase 8, transcription of nuclear factor κB (NF-κB) target genes, and p38 mitogen-activated protein (MAP) kinase activation. Thus, violacein effects resemble tumor necrosis factor α (TNF-α) signal transduction in these cells. Accordingly, infliximab, an antibody that antagonizes TNF-α–induced signaling abolished the biologic activity of violacein. Moreover, violacein directly activated TNF receptor 1 signaling, because a violacein-dependent association of TNF receptor-associated factor 2 (TRAF2) to this TNF receptor was observed in coimmunoprecipitation experiments. Hence, violacein represents the first member of a novel class of cytotoxic drugs mediating apoptosis of HL60 cells by way of the specific activation of TNF receptor 1.