title: Docosahexaenoic acid sensitizes colon cancer cells to sulindac sulfide-induced             apoptosis.
abstract: Sulindac analogs represent one of the most efficacious groups of NSAIDs             reducing the risk of colon cancer. Recent studies have shown that sulindac sulfide,             a sulindac analog effective at lower doses compared to its parent compound, triggers             the death receptor (DR)5-dependent extrinsic apoptotic pathway. Induction of apoptosis             via activation of the DR-mediated pathway would be an ideal therapeutic strategy             to eliminate cancer cells. In this study, we investigated the possibility that             colon cancer cells are sensitized to sulindac sulfide-induced apoptosis by docosahexaenoic             acid (DHA), via activation of the DR/extrinsic apoptotic pathway. Our data demonstrated             that DHA combination sensitized colon cancer cells to sulindac sulfide-induced             apoptosis, leading to enhanced growth suppression of human colon cancer xenografts.             The combination effect was primarily attributed to increased cleavage of poly(ADP-ribose)             polymerase (PARP) and caspase-8 activation. Moreover, pretreatment with z-IETD-FMK             (caspase-8 inhibitor) or stable expression of dominant negative caspase-8 genes             blocked DHA/sulindac sulfide cotreatment-induced apoptosis. In view of the finding             that DR5 silencing abrogated the combination-stimulated apoptosis, we propose             that apoptotic synergy induced by sulindac sulfide plus DHA is mediated via DR5.             Our findings collectively support the utility of a combination of sulindac sulfide             and DHA in the effective prevention and treatment of colon cancer.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University,                     Seoul, Republic of Korea.
authors.forename: Soo-Jeong
authors.initials: SJ
authors.lastname: Lim
authors.forename: Eunmyong
authors.initials: E
authors.lastname: Lee
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Lee
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Jun Hyung
authors.initials: JH
authors.lastname: Cha
authors.forename: Hwanho
authors.initials: H
authors.lastname: Choi
authors.forename: Wanseo
authors.initials: W
authors.lastname: Park
authors.forename: Hyeon Kyeom
authors.initials: HK
authors.lastname: Choi
authors.forename: Seong-Hee
authors.initials: SH
authors.lastname: Ko
authors.forename: So Hee
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000096:biosynthesis / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004281:Docosahexaenoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D061945:Caspase Inhibitors; D009842:Oligopeptides; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D013467:Sulindac; D004281:Docosahexaenoic Acids; C025462:sulindac sulfide; D011065:Poly(ADP-ribose) Polymerases; D053181:Caspase 8