Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells

Carcinogenesis, Nov 2006

The production of prostaglandin E2 (PGE2), a key proinflammatory mediator, is regulated by the availability of its substrate, arachidonic acid (AA), and the activity of the enzyme cyclooxygenase (COX). Increased PGE2 production and COX-2 expression have been observed frequently in specimens from lung cancer patients. Agents that decrease PGE2 production may prevent the initiation and progression of lung cancer. We, therefore, tested the effects of alpha-tocopherol (αTOL) analogs on PGE2 production in human lung epithelial cells. Alpha-tocopheryl succinate (αTOS), but not αTOL or alpha-tocopheryl acetate (αTOA), inhibited the phorbol 12-myristate 13-acetate (PMA)-stimulated PGE2 production in three human lung epithelial cell lines (BEAS-2B, H460 and A549 cells). The effect of these compounds on PGE2 production was not correlated with their antioxidant activities, since αTOS alone did not inhibit PMA-induced generation of reactive oxygen species. αTOS had no effect on PMA-induced AA release or COX-2 expression, although post-incubation with αTOS inhibited COX activity and prostaglandin (PGE2 and PGF2α) production in PMA-stimulated cells. αTOS also blocked the COX activity in A549 cells with endogenous high levels of COX enzymes in the absence of PMA stimulation. In addition, the ability of αTOS to inhibit COX was affected by AA concentration, suggesting that αTOS may compete with AA for interaction with COX proteins. These results suggest that αTOS inhibits COX activity, thereby inhibiting PGE2 production in human lung epithelial cells, despite the lack of antioxidant activity. Administration of αTOS may block inflammatory responses mediated by PGE2, thereby inhibiting the initiation and progression of lung cancer.

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Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells

Advance Access publication May Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells Eunmyong Lee 1 2 3 Moon-Kyung Choi 1 2 Young-Ju Lee 1 2 Ja-Lok Ku 0 2 Kyung-Hee Kim 0 2 Jin-Sung Choi 0 2 Soo-Jeong Lim 1 2 3 0 Laboratory of Cell Biology, Cancer Research Center and Cancer Research Institute, Seoul National University College of Medicine , Seoul , Korea 1 Research Institute, National Cancer Center , Goyang, Gyeonggi , Korea 2 and Biotechnology, Sejong University , 98 Kunja-dong, Kwangjin-gu, Seoul 143-747 , Korea. Tel: 3 Department of Bioscience and Biotechnology, Sejong University , Seoul , Korea - The production of prostaglandin E2 (PGE2), a key proinflammatory mediator, is regulated by the availability of its substrate, arachidonic acid (AA), and the activity of the enzyme cyclooxygenase (COX). Increased PGE2 production and COX-2 expression have been observed frequently in specimens from lung cancer patients. Agents that decrease PGE2 production may prevent the initiation and progression of lung cancer. We, therefore, tested the effects of alpha-tocopherol (aTOL) analogs on PGE2 production in human lung epithelial cells. Alphatocopheryl succinate (aTOS), but not aTOL or alphatocopheryl acetate (aTOA), inhibited the phorbol 12-myristate 13-acetate (PMA)-stimulated PGE2 production in three human lung epithelial cell lines (BEAS-2B, H460 and A549 cells). The effect of these compounds on PGE2 production was not correlated with their antioxidant activities, since aTOS alone did not inhibit PMAinduced generation of reactive oxygen species. aTOS had no effect on PMA-induced AA release or COX-2 expression, although post-incubation with aTOS inhibited COX activity and prostaglandin (PGE2 and PGF2a) production in PMA-stimulated cells. aTOS also blocked the COX activity in A549 cells with endogenous high levels of COX enzymes in the absence of PMA stimulation. In addition, the ability of aTOS to inhibit COX was affected by AA concentration, suggesting that aTOS may compete with AA for interaction with COX proteins. These results suggest that aTOS inhibits COX activity, thereby inhibiting PGE2 production in human lung epithelial cells, despite the lack of antioxidant activity. Administration of aTOS may block inflammatory responses mediated by PGE2, thereby inhibiting the initiation and progression of lung cancer. Introduction Chronic inflammation is a major contributor to the development of degenerative diseases, including cancer, cardiovascular diseases and neurodegenerative disorders (1). Inflammatory mediators such as cytokines and eicosanoids are critical for the initiation and maintenance of cancer cell survival and growth. For example, the concentration of prostaglandin E2 (PGE2) is higher in tumor tissues than in normal tissues (2). In tumor cells, PGE2 has been found to inhibit apoptosis and induce proliferation (3). PGE2 also increases tumor progression by altering cell morphology and by increasing cell motility and migration. Therefore, specific inhibition of PGE2 production may suppress tumor initiation and progression. The production of PGE2 begins with the liberation of arachidonic acid (AA) from membrane phospholipids by phospholipase A2 (PLA2). Subsequently, cyclooxygenase (COX) enzymes convert AA to PGH2 (prostagladin H2), which is converted to various prostaglandins (PGs), including PGE2. Therefore, PGE2 production can be regulated by both substrate availability and COX enzyme activity (4). Of the two isoforms of COX, COX-1 is expressed constitutively in most tissues of the body and acts as a housekeeper enzyme, whereas COX-2 is induced by cytokines, growth factors, carcinogens and tumor promoters (5). Antioxidant vitamins, which protect against oxidants such as those produced during inflammation, are believed to be important in cancer prevention, primarily by inhibiting inflammatory responses (1). Alpha-tocopherol (aTOL), one of vitamin E family members, has a potent antioxidant activity and it is the predominant form of vitamin E in vitamin supplements (6). aTOL also has antithrombotic, anticoagulant, neuroprotective, antiproliferative, immunomodulatory, cell membrane-stabilizing and antiviral actions, which may or may not be associated with its antioxidant activity (7,8). aTOL has been found to suppress PGE2 production. For example, aTOL was shown to suppress the oxidized low-density lipoprotein (LDL)-induced PLA2 activity in rat mesangial cells (9) and to attenuate lipopolysaccharide (LPS)-induced COX-2 transcription and synthesis in microglial cells (10). In macrophage cells and aged mice, aTOL and its analog alpha-tocopheryl acetate (aTOA) have been found to decrease COX activity but to have no effect on the level of expression of COX mRNA and protein (11,12). Taken together, these findings suggest that supplementation with aTOL may be beneficial in preventing diseases related to P (...truncated)


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Eunmyong Lee, Moon-Kyung Choi, Young-Ju Lee, Ja-Lok Ku, Kyung-Hee Kim, Jin-Sung Choi, Soo-Jeong Lim. Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells, Carcinogenesis, 2006, pp. 2308-2315, 27/11, DOI: 10.1093/carcin/bgl073