Induction of apoptosis in human pancreatic cancer cells by docosahexaenoic acid.

Polyunsaturated fatty acids have been indicated to induce anti-proliferative and/or apoptotic effects in various tumor cells. We showed that, at a 200- micro M concentration, both alpha-linoleic (18:2 n-6; LA) or docosahexaenoic (22:6 n-3; DHA) acid inhibited cell growth, while only DHA induced apoptosis in the human Paca-44 pancreatic cancer cell line. Investigating the mechanism underlying DHA-induced apoptosis, we showed that DHA induced a rapid and dramatic (>60%) intracellular depletion of reduced glutathione (GSH), without affecting oxidized glutathione (GSSG). Moreover, using two specific inhibitors of carrier-mediated GSH extrusion, cystathionine or methionine, we observed that GSH depletion occurred via an active GSH extrusion, and that inhibition of GSH efflux completely reversed apoptosis. These results provide the first evidence for a possible causative role of GSH depletion in DHA-induced apoptosis.