Carotenoids are compounds contained in foods and possess anticarcinogenic activity.
Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) is a promising candidate for
cancer therapeutics due to its ability to induce apoptosis selectively in
cancer cells. However, some
tumors remain tolerant to TRAIL-induced apoptosis. Therefore, it is important to develop agents that overcome this resistance. We show, for the first time, that certain
carotenoids sensitize
cancer cells to TRAIL-induced apoptosis. Combined treatment with
halocynthiaxanthin, a dietary
carotenoid contained in oysters and sea squirts, and TRAIL drastically induced apoptosis in
colon cancer DLD-1 cells, whereas each agent alone only slightly induced apoptosis. The combination induced nuclear condensation and
poly(ADP-ribose) polymerase cleavage, which are major features of apoptosis. Various
caspase inhibitors could attenuate the apoptosis induced by this combination. Furthermore, the dominant-negative form of a TRAIL receptor could block the apoptosis, suggesting that
halocynthiaxanthin specifically facilitated the TRAIL signaling pathway. To examine the molecular mechanism of the synergistic effect of the combined treatment, we did an
RNase protection assay.
Halocynthiaxanthin markedly up-regulated a TRAIL
receptor, death receptor 5 (DR5), among the
death receptor-related genes, suggesting a possible mechanism for the combined effects. Moreover, we examined whether other
carotenoids also possess the same effects.
Peridinin, but not
alloxanthin, diadinochrome, and
pyrrhoxanthin, induced DR5 expression and sensitized DLD-1 cells to TRAIL-induced apoptosis. These results indicate that the combination of certain
carotenoids and TRAIL is a new strategy to overcome TRAIL resistance in
cancer cells.