High dietary level of synthetic vitamin E on lipid peroxidation, membrane fatty acid composition and cytotoxicity in breast cancer xenograft and in mouse host tissue

Background: d-alpha-tocopherol is a naturally occurring form of vitamin E not previously known to have antitumor activity. Synthetic vitamin E (sE) is a commonly used dietary supplement consisting of a mixture of d-alpha-tocopherol and 7 equimolar stereoisomers. To test for antilipid peroxidation and for antitumor activity of sE supplementation, two groups of nude mice bearing a MDA-MB 231 human breast cancer tumor were fed an AIN-76 diet, one with and one without an additional 2000 IU/kg dry food (equivalent to 900 mg of all-rac-alpha-tocopherol or sE). This provided an intake of about 200 mg/kg body weight per day. The mice were killed at either 2 or 6 weeks after the start of dietary intervention. During necropsy, tumor and host tissues were excised for histology and for biochemical analyses. Results: Tumor growth was significantly reduced by 6 weeks of sE supplementation. Thiobarbituric acid reactive substances, an indicator of lipid peroxidation, were suppressed in tumor and in host tissues in sE supplemented mice. In the sE treated mice, the fatty acid composition of microsomal and mitochondrial membranes of tumor and host tissues had proportionately less linoleic acid (n-6 C 18-2), similar levels of arachidonic acid (n-6 C 20-4), but more docosahexanoic acid (n-3 C 22-6). The sE supplementation had no significant effect on blood counts or on intestinal histology but gave some evidence of cardiac toxicity as judged by myocyte vacuoles and by an indicator of oxidative stress (increased ratio of Mn SOD mRNA over GPX1 mRNA). Conclusions: At least one of the stereoisomers in sE has antitumor activity. Synthetic vitamin E appears to preferentially stabilize membrane fatty acids with more double bonds in the acyl chain. Although sE suppressed tumor growth and lipid peroxidation, it may have side-effects in the heart.