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 kappaB (
NF-kappaB)] 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 G(1), 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-kappaB 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.