Carcinogenesis Advance Access originally published online on December 12, 2005
Carcinogenesis 2006 27(3):508-516; doi:10.1093/carcin/bgi307
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Carcinogenesis vol.27 no.3 © Oxford University Press 2005; all rights reserved.
Violacein synergistically increases 5-fluorouracil cytotoxicity, induces apoptosis and inhibits Akt-mediated signal transduction in human colorectal cancer cells
Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands, 1 Biological Chemistry Laboratory, Instituto de Quimica, Universidade Estadual de Campinas and NCA Universidade de Mogi das Cruzes, S.P., Brazil, 2 Department of Cell Biology, University of Groningen, Groningen, The Netherlands, 3 Departamento de Bioquimica, Universidade Estadual de Campinas, Brazil and 4 Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
* To whom correspondence should be addressed at: Laboratory for Experimental Internal Medicine, G2-105, Academic Medical Center Amsterdam, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands. Tel: +31 20 566 8781; Fax: +31 20 697 7192; Email: l.kodach{at}amc.uva.nl
Despite recent additions to the armory of chemotherapeutic agents for colorectal cancer (CRC) treatment, the results of chemotherapy remain unsatisfactory. 5-Fluorouracil (5-FU) still represents the cornerstone of treatment and resistance to its actions is a major obstacle to successful chemotherapy. Therefore, new active agents in CRC and agents that increase the chemosensitivity of cancer cells to 5-FU are still urgently required. Violacein, a pigment isolated from Chromobacterium violaceum in the Amazon river, has a diverse spectrum of biological activities, and represents a novel cytotoxic drug with known antileukemic properties. To assess the suitability of violacein as a chemotherapeutic agent in CRC its cytotoxic effects were evaluated both as a single agent and in combination with 5-FU. Its underlying mechanisms of action were further investigated by studying its effects on the cell cycle, apoptosis and cell survival pathways [phosphatidylinositol-3-kinase/Akt, p44/42 mitogen activated protein kinase and nuclear factor 
B (NF-B)] in colon cancer cell lines. Violacein inhibits the growth of all four colon cancer cell lines tested. It induces apoptosis, and potentiates the cytotoxic effect of 5-FU in a poorly differentiated microsatellite unstable cell line (HCT116). Violacein causes cell cycle block at G1, upregulates p53, p27 and p21 levels and decreases the expression of cyclin D1. Violacein leads to dephosphorylation of retinoblastoma protein and activation of caspases and a pancaspase inhibitor abrogates its biological activity. Our data provide evidence that violacein acts through the inhibition of Akt phosphorylation with subsequent activation of the apoptotic pathway and downregulation of NF-B signaling. This leads to the increase in chemosensitivity to 5-FU in HCT116 colon cancer cells. Taken together, our findings suggest that violacein will be active in the treatment of colorectal tumors and offers new prospects for overcoming 5-FU resistance.
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  K. S. Ryan, C. J. Balibar, K. E. Turo, C. T. Walsh, and C. L. Drennan The Violacein Biosynthetic Enzyme VioE Shares a Fold with Lipoprotein Transporter Proteins J. Biol. Chem., March 7, 2008; 283(10): 6467 - 6475. [Abstract] [Full Text] [PDF]
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