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

Abstract

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.

Omega-3 fatty acids, membrane remodeling and cancer prevention

“…Benefits of dietary n-3 PUFA adjunct to FDA approved drugs in cancer treatment or prevention have been reported. For example, DHA combination sensitized colon cancer cells to non-steroidal anti-inflammatory drug (sulindac sulfide)-induced apoptosis, leading to enhanced growth suppression of human colon cancer xenografts (Lim et al, 2012). This noteworthy, because NSAIDs are one of the most efficacious classes of drugs used to reduce the risk of colon cancer.…”

Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid

“…For example, a combination of the selective COX-2 inhibitor celecoxib and DHA led to decreased proliferation and increased apoptosis of HCA-7 human CRC cells [34]. Moreover, combined DHA and sulindac (a non-selective COX inhibitor) treatment decreased growth and increased apoptosis of three human CRC cell lines compared with either agent alone [35].…”

Docosahexaenoic Acid Inhibits Proliferation of EoL-1 Leukemia Cells and Induces Cell Cycle Arrest and Cell Differentiation

“…The antineoplastic activity of DHA has been indicated in many studies. DHA induces apoptosis and differentiation in human melanoma cells in vitro [26], helps prevent colorectal cancer [19], induces apoptotic cell death in human cancer cells either alone or in combination with conventional therapies, and causes selective cytotoxicity towards cancer cells with little or no toxicity on normal cells [27]. DHA can induce apoptosis in tumor cells in vitro and in vivo, in a dose- and time-dependent manner in tumor cell lines derived from a wide range of solid tumors.…”

“…Many studies have shown that docosahexaenoic acid exhibits a time- and concentration-dependent antiproliferative effect on various human cancer cell lines while having minimal cytotoxicity on the normal or non-tumorigenic cells [5,17], cause cell cycle arrest, or even apoptosis and presents synergistic anticancer properties with other drug substances [1,18,19]. Enormous data from cancer cell lines and in vivo cancer models have given insight into the mechanisms underlying the anticancer effects of ω-3 PUFAs [20,21].…”