Journal Article

Violacein synergistically increases 5-fluorouracil cytotoxicity, induces apoptosis and inhibits Akt-mediated signal transduction in human colorectal cancer cells

Liudmila L. Kodach, Carina L. Bos, Nelson Durán, Maikel P. Peppelenbosch, Carmen V. Ferreira and James C.H. Hardwick

in Carcinogenesis

Volume 27, issue 3, pages 508-516
Published in print March 2006 | ISSN: 0143-3334
Published online December 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi307
Violacein synergistically increases 5-fluorouracil cytotoxicity, induces apoptosis and inhibits Akt-mediated signal transduction in human colorectal cancer cells

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  • Clinical Cytogenetics and Molecular Genetics

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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 κB (NF-κB)] 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-κB 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.

Keywords: CI, combination index; CRC, colorectal cancer; DMSO, dimethyl sulfoxide; 5-FU, 5-fluorouracil; GSK-3α/β, glycogen synthase kinase 3α/β; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κB; PBS, phosphate-buffered saline; PI3 kinase, phosphatidylinositol-3-kinase; Rb, retinoblastoma protein

Journal Article.  6125 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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