title: Differential sensitivity of cancer cells to docosahexaenoic acid-induced cytotoxicity: the potential importance of down-regulation of superoxide dismutase 1 expression.
abstract: Docosahexaenoic acid (DHA, 22:6 n-3), a polyunsaturated fatty acid found in fish oil, exerts cytotoxic effects on cancer cells. Although DHA was toxic toward five human cancer cell lines (MCF-7, MDA-MB-231, SiHa, Raji, and DHL-4), the lines were not uniformly sensitive. DHL-4, a bcl-2 overexpressing lymphoid line, was the most sensitive (IC50, 5.2 micromol/L) and the cervical cancer cell line, SiHa, was the most resistant (IC50, >300 micromol/L). Lipid peroxidation has been cited by others as an important component of DHA toxicity, and we confirmed that vitamin E prevents the cytotoxic effects of DHA. Lipid peroxidation was greater following DHA treatment of the sensitive DHL-4 cells than in the resistant SiHa cells, as assessed by thiobarbituric acid reactive substance generation. DHL-4 cells treated with DHA for 20 hours showed a 3.5-fold increase in thiobarbituric acid reactive substances, whereas SiHa cells showed no increase. Reverse transcription-PCR analysis detected a down-regulation of the expression of the major antioxidant enzyme, superoxide dismutase (SOD) 1, in DHL-4 cells but not in SiHa cells after DHA treatment. Knockdown of SOD1 expression in SiHa cells with small interfering RNA significantly enhanced lipid peroxidation and cytotoxicity on exposure to DHA. These results show that DHL-4 cells are highly sensitive to the cytotoxic effect of DHA and that regulation of SOD1 expression may play an important role in determining the sensitivity of different tumor cells to the cytotoxic effects of DHA.
authors.affiliation: University of Oklahoma Health Sciences Center, 975 Northeast 10th Street, BRC-409, Oklahoma City, OK 73104, USA.
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Ding
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Vaught
authors.forename: Hanako
authors.initials: H
authors.lastname: Yamauchi
authors.forename: Stuart E
authors.initials: SE
authors.lastname: Lind
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D002374:Catalase / Q000378:metabolism; D002470:Cell Survival; D004281:Docosahexaenoic Acids / Q000633:toxicity*; D015536:Down-Regulation; D005979:Glutathione Peroxidase / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D014407:Tumor Cells, Cultured; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; C000606290:SOD1 protein, human; D004281:Docosahexaenoic Acids; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human