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

Abstract

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.

Evaluation of in Vitro Cytotoxic Effect of Violacein Produced by Novel Isolate Chromobacterium Vaccinii Cv5 Against the Cervical and Lung Cancer Cell

“…Kodach et al [15] show that the violacein (IC 50 1-2 µM) is a promising chemotherapeutic agent that acts by blocking AKT activation and inducing apoptosis thus increasing the chemosensitivity of colon cancer cells to 5-fluorouracil treatment. Ferreira et al [16] in their study investigate the effect of violacein in leukemia (HL60) cell.…”

Smad4 sensitizes colorectal cancer to 5-fluorouracil through cell cycle arrest by inhibiting the PI3K/Akt/CDC2/survivin cascade

“…To the best of our knowledge, there is little research regarding the mechanism of Smad4 in inducing chemosensitivity. To reveal the mechanism, we focused on the non-Smad signals which were regulated by Smad4 expression, as several nonSmad signals contribute to chemosensitivity, with the MEK/ ERK and PI3K/Akt pathway being well elucidated (23)(24)(25)(26)(27)(28)(29). There is much controversy regarding the effect of the MEK/ ERK pathway on chemotherapeutic drug-induced apoptosis.…”

Influence of Environmental Factors on the Production of Violacein Synthesized By Janthinobacterium lividum

“…Violacein is a purple pigment product of the secondary metabolism of bacteria, whose biological activities have been widely reported, including antimicrobial activity (antibacterial, antiviral, antiprotozoal and antifungal) [3,4,[6][7][8][9][10][11][12][13][14] anticancer activity [15][16][17][18][19] antioxidant activity [20] and recent studies also show insecticidal activity [5]. Due to its biotechnological potential, numerous studies have been done indicating that Chromobacterium violaceum and Janthinobacterium lividum are primarily responsible for its synthesis [3][4][5]9,21,22].…”

“…Due to its biotechnological potential, numerous studies have been done indicating that Chromobacterium violaceum and Janthinobacterium lividum are primarily responsible for its synthesis [3][4][5]9,21,22]. Violacein has an indole derivative structure [8,15,17,18,21] characterized as C20-H13-N3-O3 [4,22,23]. The pigment is insoluble in water but soluble in alcohols (methanol, ethanol) and acetone.…”