Anti-tumor effects of fucoxanthin isolated from Ishige okamurae and analysis of related signaling pathway

Abstract

Fucoxanthin, a major carotenoid of edible brown algae, has reported to have potent anti-tumor activity both in vitro and in vivo. However, the mechanism underlying fucoxanthin-induced apoptosis in HL-60 and B16F10 cell lines remains unclear. In the present study, we designed to evaluate the molecular mechanism of fucoxanthin isolated from a marine alga, Ishige okamurae against HL-60 and B16F10 cell lines. We found that reactive oxygen species (ROS) are generated during fucoxanthin-induced apoptosis in HL-60 cells, and N-acetylcysteine (NAC) which is a scavenger of ROS, suppressed fucoxantin-induced cytotoxicity and apoptosis. Furthermore, the treatment with NAC dramatically inhibited fucoxanthin-induced phosphorylation of JNK and p38 kinase in HL-60 cells. Moreover, fucoxanthin reduced the viability of B16F10 cells in a dose-dependent manner accompanied by the induction of cell cycle arrest during the G0/G1 phase and apoptosis. Fucoxanthin-induced G0/G1 arrest was associated with a marked decrease in the protein expressions of phosphorylated-Rb (retinoblastoma protein), cyclin D (1 and 2) and cyclin-dependent kinase (Cdk)4 and up-regulation of the protein levels of p15INK4B and p27Kip1. Fucoxanthin-induced apoptosis was accompanied with down-regulation of the protein levels of Bcl-xL, and inhibitor of apoptosis protein (XIAP), resulting in cytochrome c release and sequential activation of caspase-9, caspase-3, and PARP. Furthermore, fucoxanthin activated c-Jun N-terminal kinase (JNK), p38 MAPK (p38) and extracellular signal-regulated kinase (ERK) on B16F10 cells in a time-dependent manner. These results suggest that fucoxanthin has anti-tumor effects on HL-60 and B16F10 cell lines by inducing selectively the genes related to apoptosis which provided further theoretical support for the application of fucoxanthin as a promising anti-tumor agent.