Docosahexaenoic acid sensitizes colon cancer cells to sulindac sulfide-induced apoptosis

• Published in: Oncology reports Vol. 27; no. 6; pp. 2023 - 2030
• Main Authors: LIM, Soo-Jeong, LEE, Eunmyong, LEE, Eun-Hye, KIM, Soo-Yeon, JUN HYUNG CHA, HWANHO CHOI, PARK, Wanseo, HYEON KYEOM CHOI, KO, Seong-Hee, SO HEE KIM
• Format: Journal Article
• Language: English
• Published: Athens Spandidos 01.06.2012
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Caspase 8 - biosynthesis; Caspase 8 - metabolism; Caspase Inhibitors; Cell Line, Tumor; Cell Proliferation - drug effects; Colonic Neoplasms - drug therapy; Docosahexaenoic Acids - pharmacology; Docosahexaenoic Acids - therapeutic use; Drug Synergism; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Medical sciences; Mice; Mice, Inbred BALB C; Oligopeptides - pharmacology; Poly(ADP-ribose) Polymerases - metabolism; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; RNA Interference; RNA, Small Interfering; Signal Transduction - drug effects; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Sulindac - analogs & derivatives; Sulindac - pharmacology; Sulindac - therapeutic use; Tumors; Xenograft Model Antitumor Assays; Prostaglandin-endoperoxide synthase; Enzyme; Enzyme inhibitor; Polyunsaturated fatty acid; Lipids; Malignant tumor; Acetic acid derivative; Docosahexaenoic acid; n-3 fatty acid; Colonic disease; Sulfides; Colon cancer; Cancerology; Cell death; Sulindac; Death receptor; Digestive diseases; Intestinal disease; Indene derivatives; Oxidoreductases; Tumor cell; Cancer; Apoptosis
• ISSN: 1021-335X; 1791-2431
• DOI: 10.3892/or.2012.1706

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.