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Induction of Apoptosis in Human Pancreatic Cancer Cells by Docosahexaenoic Acid


N MERENDINOa, R MOLINARIa, B LOPPIa, G PESSINAa, M D' AQUINOb, G TOMASSIa AND F VELOTTIA aDepartment of Environmental Sciences, Tuscia University, Viterbo, Italy
bNational Institute for Food and Nutrition Research (INRAN), Rome, Italy
Address for correspondence: Nicolò Merendino, Laboratory of Immunology and Nutrition, Department of Environmental Sciences, Largo dell'Università, Tuscia University, 01100 Viterbo, Italy. Voice: +39-0761-357133; fax: +39-0761-357134. merendin@unitus.it
Ann. N.Y. Acad. Sci. 1010: 361-364 (2003).


Polyunsaturated fatty acids have been indicated to induce anti-proliferative and/or apoptotic effects in various tumor cells. We showed that, at a 200-µM 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.

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