Molecular mechanism of violacein-mediated human leukemia cell death

Abstract

Violacein, a pigment isolated from Chromobacterium violaceum in 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 B (NF-B) target genes, and p38 mitogenactivated protein (MAP) kinase activation. Thus, violacein effects resemble tumor necrosis factor ␣ (TNF-␣) signal transduction in these cells. Accordingly, infliximab, an antibody that antagonizes TNF-␣-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. IntroductionViolacein ( Figure 1A), a purple-colored pigment produced by one of the strains of Chromobacterium violaceum found in the Amazon River, Brazil, is an indole derivative characterized as 3-(1,2-dihydro-5-(5-hydroxy-1H-indol-3-yl)-2-oxo-3H-pyrrol-3-ilydene)-1,3-dihydro-2H-indol-2-one. 1 The biosynthesis and biologic properties of this pigment have been extensively studied; in particular, its antitumoral, antibacterial, antiulcerogenic, antileishmanial, and antiviral activities are of interest. [1][2][3][4][5][6] Its activity on acute myeloblastic leukemia (HL60) cells is of special interest because the compound effectively induces cell death in these cells.The development of violacein as a possible novel therapeutic avenue for the treatment of leukemia, however, depends on the establishment of the molecular basis for this cytotoxicity. Evidently, a possible future application of violacein as a therapeutic agent critically depends on its ability to target leukemia cells more effectively than normal blood cells. Hence, research comparing the cytotoxicity of violacein in transformed cells and the corresponding untransformed ones is urgently called for. In addition, identification of the molecular details mediating violacein effects on leukemic cells will provide insight into the possible benefit of this compound in comparison to existing therapeutics.The above-mentioned considerations prompted us to investigate the effects of violacein in HL60 cells. This cell line is generally accepted as a valid model for studying myeloid leukemia biology. 7,8 Melo et al 6 showed earlier that HL60 cells react to violacein with bo...

Evaluation of in Vitro Cytotoxic Effect of Violacein Produced by Novel Isolate Chromobacterium Vaccinii Cv5 Against the Cervical and Lung Cancer Cell

“…Kodach et al [15] show that the violacein (IC 50 1-2 µM) is a promising chemotherapeutic agent that acts by blocking AKT activation and inducing apoptosis thus increasing the chemosensitivity of colon cancer cells to 5-fluorouracil treatment. Ferreira et al [16] in their study investigate the effect of violacein in leukemia (HL60) cell. They demonstrated that violacein from Chromobacterium violaceum represents the first member of a novel class of cytotoxic drugs mediating apoptosis of HL60 cells by way of the specific activation of tumor necrosis factor receptor 1 and caspases.…”

The Medicinal Value of Biodiversity: New Hits to Fight Cancer

“…Of note, this purple-colored pigment has gained attention for its antitumor properties, which has been demonstrated in vitro against a number of cancer cell lines from several histological origins, as well as in vivo (Melo et al, 2003;Ferreira et al, 2004;Kodach et al, 2006;Durán et al, 2007;Bromberg et al, 2010). Moreover, studies have shown the ability of violacein to induce apoptosis by mechanisms that include modulation of a number of signaling pathways and the generation of oxidative stress (Melo et al, 2003;Ferreira et al, 2004;Kodach et al, 2006;Durán et al, 2007;Bromberg et al, 2010). Importantly, treatment of Ehrlich ascites tumor (EAT)-bearing mice with micromolar doses of violacein inhibited the tumor volume, the number of viable tumor cells and increased survival, differing from other works with natural products in the literature which spend high doses of the compounds.…”

Isolation and characterization of pigmented bacteria showing antimicrobial activity from Malaysian marine environment

“…Pigment like prodigiosin (red), violacein (violet), and pyocianin (blue-green) are known to have active compounds such as anitimicrobial activity, antiviral, antitumor, antiprotozoa, antioxidant, anticancer and much more (Ferreira et al, 2004;Matz et al, 2004;Deorukhkar et al, 2007;Kim et al, 2010). It is crucial to pin-point the adherence of pigment in bacteria, which is for industrial applications.…”