Growth inhibition and pro-apoptotic activity of violacein in Ehrlich ascites tumor

Growth inhibition and pro-apoptotic activity of violacein in Ehrlich ascites tumor

Author Bromberg, Natalia Google Scholar
Dreyfuss, Juliana L. Autor UNIFESP Google Scholar
Regatieri, Caio V. Autor UNIFESP Google Scholar
Palladino, Marcelly V. Autor UNIFESP Google Scholar
Duran, Nelson Google Scholar
Nader, Helena B. Autor UNIFESP Google Scholar
Haun, Marcela Google Scholar
Justo, Giselle Z. Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Universidade Estadual de Campinas (UNICAMP)
Abstract The continuing threat to biodiversity lends urgency to the need of identification of sustainable source of natural products. This is not so much trouble if there is a microbial source of the compound. Herein, violacein, a natural indolic pigment extracted from Chromobacterium violaceum, was evaluated for its antitumoral potential against the Ehrlich ascites tumor (EAT) in vivo and in vitro. Evaluation of violacein cytotoxicity using different endpoints indicated that EAT cells were twofold (IC(50) = 5.0 mM) more sensitive to the compound than normal human peripheral blood lymphocytes. in vitro studies indicated that violacein cytotoxicity to EAT cells is mediated by a rapid (8-12 h) production of reactive oxygen species (ROS) and a decrease in intracellular GSH levels, probably due to oxidative stress. Additionally, apoptosis was primarily induced, as demonstrated by an increase in Annexin-V positive cells, concurrently with increased levels of DNA fragmentation and increased caspase-2. caspase-9 and caspase-3 activities up to 4.5-, 6.0- and 5.5-fold, respectively, after 72 h of treatment. Moreover, doses of 0.1 and 1.0 mu g kg(-1) violacein, administered intraperitoneally (i.p.) to EAT-bearing mice throughout the lifespan of the animals significantly inhibited tumor growth and increased survival of mice. in view of these results, a 35-day toxicity study was conducted in vivo. Complete hematology, biochemistry (ALT, AST and creatinine levels) and histopathological analysis of liver and kidney indicated that daily doses of violacein up to 1000 mg kg(-1) for 35 days are well tolerated and did not cause hematotoxicity not renal or hepatotoxicity when administered i.p. to mice. Altogether, these results indicate that violacein causes oxidative stress and an imbalance in the antioxidant defense machinery of cells culminating in apoptotic cell death. Furthermore, this is the first report of its antitumor activity in vivo, which occurs in the absence of toxicity to major organs. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
Keywords Ehrlich ascites tumor
Chromobacterium violaceum
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number FAPESP: 00/08422-1
Date 2010-06-07
Published in Chemico-biological Interactions. Clare: Elsevier B.V., v. 186, n. 1, p. 43-52, 2010.
ISSN 0009-2797 (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 43-52
Access rights Closed access
Type Article
Web of Science ID WOS:000278801500007

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