title: Halocynthiaxanthin and peridinin sensitize colon cancer cell lines to tumor necrosis factor-related apoptosis-inducing ligand.
abstract: 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.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Takashi
authors.initials: T
authors.lastname: Maoka
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kanazawa
authors.forename: Mano
authors.initials: M
authors.lastname: Horinaka
authors.forename: Miki
authors.initials: M
authors.lastname: Wakada
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Satomi
authors.forename: Hoyoku
authors.initials: H
authors.lastname: Nishino
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis; D002338:Carotenoids / Q000378:metabolism / Q000494:pharmacology; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D024341:Xanthophylls / Q000494:pharmacology*
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; D024341:Xanthophylls; C520451:pyrrhoxanthin; C016040:peridinin; D002338:Carotenoids; C073045:halocynthiaxanthin; D011065:Poly(ADP-ribose) Polymerases; C006462:alloxanthin; D015107:4-Butyrolactone