Carcinogenesis Advance Access published online on December 12, 2005
Carcinogenesis, doi:10.1093/carcin/bgi307
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1 Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
* To whom correspondence should be addressed. Despite recent additions to the armory of chemotherapeutic agents for colorectal cancer 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 colorectal cancer 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 colorectal cancer 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 (PI3 kinase/Akt, p44/42 MAP kinase and nuclear factor kappa-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 Rb 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 NFkB signaling. This leads to the increase of 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.
Received August 29, 2005
Revised November 22, 2005
Accepted December 6, 2005
CANCER BIOLOGY
Violacein synergistically increases 5-fluorouracil cytotoxicity, induces apoptosis and inhibits Akt-mediated signal transduction in human colorectal cancer cells
Liudmila L. Kodach 1 *,
Carina L. Bos 1,
Nelson Durán 2,
Maikel P. Peppelenbosch 3,
Carmen V. Ferreira 4,
and
James C. H. Hardwick 5
2 Biological Chemistry Laboratory, Instituto de Quimica, Universidade Estadual de Campinas; NCA Universidade de Mogi das Cruzes, S.P., Brazil
3 Department of Cell Biology, University of Groningen, Groningen, The Netherlands
4 Departamento de Bioquimica, Universidade Estadual de Campinas, Brazil
5 Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
Liudmila L. Kodach, E-mail: l.kodach{at}amc.uva.nl
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