Cytotoxic Effect of the Diterpene Lactone Dehydrocrotonin from <i>Croton cajucara</i> on Human Promyelocytic Leukemia Cells

Freire, Ana Claudia Galvão; Melo, Patrı́cia da Silva; Aoyama, Hiroshi; Haun, Marcela; Durán, Nélson; Ferreira, Carmen Verı́ssima

doi:10.1055/s-2003-37036

Cited by 24 publications

(14 citation statements)

References 12 publications

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“…[16][17][18][19] Violacein could be an interesting candidate for cancer treatment because of its cytotoxic effect at low concentration on different transformed cell lines, and it seems especially promising with respect to leukemia. 1,6 The development of violacein to treat cancerous disease is limited, however, by a lack of rational insight into the molecular mechanisms by which violacein affects leukemic cell physiology as well as the specificity of these mechanisms to HL60 cells in comparison to K562, U937, and untransformed cells.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanism of violacein-mediated human leukemia cell death

Ferreira

Bos

Versteeg

et al. 2004

Blood

133

114

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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...

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Section: Discussionmentioning

confidence: 99%

Molecular mechanism of violacein-mediated human leukemia cell death

Ferreira

Bos

Versteeg

et al. 2004

Blood

133

114

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“…This toxicity is probably attributable, at least in part, to the presence of cytotoxic terpenoids in C. mubango. All Croton species probably have some mammalian toxicity because of the terpenic compounds, such as crotonin and derivatives, that they contain (Rodriguez and Haun, 1999;Block et al, 2002;Melo et al, 2002;Albino de Almeida et al, 2003;Friere et al, 2003;Gadir Abdel et al, 2003).…”

Section: Croton Mubangomentioning

confidence: 99%

Antimalarial activities and toxicities of three plants used as traditional remedies for malaria in the Democratic Republic of Congo:Croton mubango , Nauclea pobeguiniiandPyrenacantha staudtii

Mesia

Tona

Penge

et al. 2005

Annals of Tropical Medicine & Parasitology

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The antimalarial activities of crude extracts and 17 fractions from the partition of 80%-methanolic extracts of three plants (the stem bark of Croton mubango, the stem bark of Nauclea pobeguinii and the leaves of Pyrenacantha staudtii) used as antimalarial remedies in the Democratic Republic of Congo were studied both in vitro (against Plasmodium falciparum) and in mice infected with Pl. berghei berghei. The toxic effects of dried aqueous extracts of the plants were also investigated, in uninfected mice. The most active crude extracts in vitro, with median inhibitory concentrations (IC(50)) of <1 microg/ml, were found to be the methanolic and dichloromethane extracts of C. mubango, and the dichloromethane extracts of N. pobeguinii and Py. staudtii. The aqueous extract with the most antimalarial activity in vitro was that of C. mubango (IC(50) = 3.2 microg/ml), followed by that of N. probeguinii (IC(50) = 5.3 microg/ml) and then that of Py. staudii (IC(50) = 15.2 microg/ml). Results from the in-vivo tests of antimalarial activity showed that, at a daily oral dose of 200 mg/kg, all the dichloromethane extracts, the petroleum-ether, chloroformic, ethyl-acetate and residual water-soluble fractions from C. mubango, and the chloroformic, ethyl-acetate and n-butanolic fractions from Py. staudtii produced >80% chemosuppression of the parasitaemias by day 4. The aqueous extracts of C. mubango and N. probeguinii produced a slightly lower but still significant inhibition of parasitaemia (60%-80%) whereas that of Py. staudtii only suppressed the day-4 parasitaemias by 37%. The dried aqueous extract of the stem bark of C. mubango showed some signs of toxicity in mice, with median lethal doses (LD(50)) of 350 mg/kg in the female mice and 900 mg/kg in the male. The extract significantly increased the serum concentrations of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) in mice of both sexes, but had no effect on the blood levels of creatinine or urea. No significant toxic effect was observed for the dried aqueous extracts of N. pobeguinii and Py. staudtii (LD(50) >5 g/kg). Neither of these extracts affected the serum concentrations of GPT or the blood concentrations of creatinine and urea, although the N. pobeguinii extract did increase the serum concentration of GOT.

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“…Amongst such plants already studied are Croton lechleri (Rossi et al, 2003), Croton cajucara Hiruma-Lima et al, 2002a, 2002bFreire et al, 2003), and Croton urucurana (Gurgel et al, 2001). Some species of Croton present multiple activities, such as Croton cajucara, for which cytotoxic (Freire et al, 2003), gastroprotective (Hiruma-Lima et al, 2002a, 2002b, antiulcerogenic (Hiruma-Lima et al, 2002b), glucose-and triglyceridelowering and antigenotoxic (Agner et al, 2001) activities have been described. Besides the cited studies, many others are in development concerning the biological activities of extracts, fractions and active components from the plants of this genus.…”

Section: Introductionmentioning

confidence: 99%