REVIEW: Enhancement of Nitric Oxide and Superoxide Generations by alpha-Tocopheryl Succinate and Its Apoptotic and Anticancer Effects

K. Fukuzawa^*, K. Kogure, M. Morita, S. Hama, S. Manabe, and A. Tokumura

Faculty of Pharmaceutical Sciences, Tokushima University, Tokushima 770-8505, Japan; fax: +81-88-633-9572; E-mail: fukuzawa@ph.tokushima-u.ac.jp

^* To whom correspondence should be addressed.

Received April 30, 2003

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Tocopheryl succinate (TS), a succinyl ester of beta-tocopherol (beta-T), has been reported to have various biological activities. In this communication, we review the current findings about TS including our recent studies of its effects on nitric oxide (NO) and superoxide (O₂^-) generations implicated in cancer and atherosclerosis. First, we investigated the effect of TS on NO production in vascular smooth muscle cells (VSMC) under atherosclerosis-like conditions using lipopolysaccharide (LPS) and interferon-beta (IFN). TS enhanced LPS/IFN-dependent NO production, but beta-T itself did not. The enhancement by TS of NO production was inhibited by beta-T but not by antioxidants such as ascorbic acid and 2[3]-t-butyl-4-hydroxyanisole (BHA). TS enhanced the amount of protein kinase Cbeta (PKCbeta) in VSMC, and PKC inhibitors inhibited TS-enhanced NO production, suggesting that the enhancing effect of TS on NO production is caused by up-regulation of PKC. Second, we found that TS induced apoptosis in VSMC associated with increase in O₂^- generation via NADPH-dependent oxidase. We further observed that a mouse breast cancer cell line C127I was more susceptible for TS-induced apoptosis than a mouse breast normal cell line NmuMG, and that superoxide dismutase, beta-T, and BHA inhibited TS-caused morphological cell damage in C127I. From these results, O₂^- itself and/or other reactive oxygen species are assumed to associate with TS-induced cell toxicity, and antioxidative defense systems are supposed to be lowered in cancer cells. Finally, we found that intravenous injection of TS vesicles completely inhibited the growth of melanoma cells B16-F1 inoculated on the back of hairless mice and enhanced their survival time.

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KEY WORDS: beta-tocopheryl succinate, vitamin E, nitric oxide, superoxide, apoptosis, atherosclerosis, cancer cells, anticancer drug

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