Biochemistry (Moscow)

, Volume 81, Issue 8, pp 806–818 | Cite as

α-Tocopheryl succinate affects malignant cell viability, proliferation, and differentiation



The widespread occurrence of malignant tumors motivates great attention to finding and investigating effective new antitumor preparations. Such preparations include compounds of the vitamin E family. Among them, α-tocopheryl succinate (vitamin E succinate (VES)) has the most pronounced antitumor properties. In this review, various targets and mechanisms of the antitumor effect of vitamin E succinate are characterized. It has been shown that VES has multiple intracellular targets and effects, and as a result VES is able to induce apoptosis in tumor cells, inhibit their proliferation, induce differentiation, prevent metastasizing, and inhibit angiogenesis. However, VES has minimal effects on normal cells and tissues. Due to the variety of targets and selectivity of action, VES is a promising agent against malignant neoplasms. More detailed studies in this area can contribute to development of effective and safe chemotherapeutic preparations.


α-tocopheryl succinate apoptosis reactive oxygen species mitochondria tumor cells 





glycerol-3-phosphate dehydrogenase


reactive oxygen species


succinate dehydrogenase


superoxide dismutase


vitamin E succinate


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  1. 1.
    Rodriguez-Enriquez, S., Marin-Hernandez, A., GallardoPerez, J. C., Carreno-Fuentes, L., and Moreno-Sanchez, R. (2009) Targeting of cancer energy metabolism, Mol. Nutr. Food Res., 53, 29–48.PubMedCrossRefGoogle Scholar
  2. 2.
    Dong, L. F., Jameson, V. J., Tilly, D., Cerny, J., and Mahdavian, E. (2011) Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II, J. Biol. Chem., 286, 3717–3728.PubMedCrossRefGoogle Scholar
  3. 3.
    Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G., and Gluud, C. (2012) Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases, Cochrane Database Syst. Rev., 3, CD007176.PubMedGoogle Scholar
  4. 4.
    Evans, H. M., and Bishop, K. S. (1922) On the existence of a hitherto unrecognized dietary factor essential for reproduction, Science, 56, 650–651.PubMedCrossRefGoogle Scholar
  5. 5.
    Rizvi, S., Raza, S. T., Ahmed, F., Ahmad, A., Abbas, S., and Mahdi, F. (2014) The role of vitamin E in human health and some diseases, Sultan Qaboos Univ. Med. J., 14, 157–165.Google Scholar
  6. 6.
    Singh, C. K., Ndiaye, M. A., Siddiqui, I. A., Nihal, M., Havighurst, T., Kim, K., Zhong, W., Mukhtar, H., and Ahmad, N. (2014) Methaneseleninic acid and γ-tocopherol combination inhibits prostate tumor growth in vivo in a xenograft mouse model, Oncotarget, 5, 3651–3661.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Ju, J., Hao, X., Lee, M. J., Lambert, J. D., Lu, G., Xiao, H., Newmark, H. L., and Yang, C. S. (2009) A gammatocopherol-rich mixture of tocopherols inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice, Cancer Prev. Res. (Philadelphia), 2, 143–152.CrossRefGoogle Scholar
  8. 8.
    Stone, W. L., Krishnan, K., Campbell, S. E., and Palau, V. E. (2014) The role of antioxidants and pro-oxidants in colon cancer, World J. Gastrointest. Oncol., 6, 55–66.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Jiang, Q., Jiang, Z., Hall, Y. J., Jang, Y., Snyder, P. W., Bain, C., Huang, J., Jannasch, A., Cooper, B., Wang, Y., and Moreland, M. (2013) Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice, Free Radic. Biol. Med., 65, 1069–1077.PubMedCrossRefGoogle Scholar
  10. 10.
    McIntyre, B. S., Briski, K. P., Gapor, A., and Sylvester, P. W. (2000) Antiproliferative and apoptotic effects of tocopherols and tocotrienols on preneoplastic and neoplastic mouse mammary epithelial cells, Proc. Soc. Exp. Biol. Med., 224, 292–301.PubMedCrossRefGoogle Scholar
  11. 11.
    Neuzil, J., Weber, T., Schroder, A., Lu, M., Ostermann, G., Gellert, N., Mayne, G. C., Olejnicka, B., Negre-Salvayre, A., Sticha, M., Coffey, R. J., and Weber, C. (2001) Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements, FASEB J., 15, 403–415.PubMedCrossRefGoogle Scholar
  12. 12.
    Birringer, M., EyTina, J. H., Salvatore, B. A., and Neuzil, J. (2003) Vitamin E analogues as inducers of apoptosis: structure–function relation, Br. J. Cancer, 88, 1948–1955.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Shibata, A., Nakagawa, K., Sookwong, P., Tsuduki, T., Asai, A., and Miyazawa, T. (2010) α-Tocopherol attenuates the cytotoxic effect of δ-tocotrienol in human colorectal adenocarcinoma cells, Biochem. Biophys. Res. Commun., 397, 214–219.PubMedCrossRefGoogle Scholar
  14. 14.
    Campbell, S. E., Stone, W. L., Lee, S., Whaley, S., Yang, H., Qui, M., Goforth, P., Sherman, D., McHaffie, D., and Krishnan, K. (2006) Comparative effects of RRR-alphaand RRR-gamma-tocopherol on proliferation and apoptosis in human colon cancer cell lines, BMC Cancer, 6, 13.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Miller, E. R., 3rd, Pastor-Barriuso, R., Dalal, D., Riemersma, R. A., Appel, L. J., and Guallar, E. (2005) Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality, Ann. Intern. Med., 142, 37–46.PubMedCrossRefGoogle Scholar
  16. 16.
    Gunawardena, K., Murray, D. K., and Meikle, A. W. (2000) Vitamin E and other antioxidants inhibit human prostate cancer cells through apoptosis, Prostate, 44, 287–295.PubMedCrossRefGoogle Scholar
  17. 17.
    Pastori, M., Pfander, H., Boscoboinik, D., and Azzi, A. (1998) Lycopene in association with alpha-tocopherol inhibits at physiological concentrations proliferation of prostate carcinoma cells, Biochem. Biophys. Res. Commun., 250, 582–585.PubMedCrossRefGoogle Scholar
  18. 18.
    Mahabir, S., Schendel, K., Dong, Y. Q., Barrera, S. L., Spitz, M. R., and Forman, M. R. (2008) Dietary alpha-, beta-, gammaand delta-tocopherols in lung cancer risk, Int. J. Cancer, 123, 1173–1180.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Prasad, K. N., and Edwards-Prasad, J. (1992) Vitamin E and cancer prevention: recent advances and future potentials, J. Am. Coll. Nutr., 11, 487–500.PubMedCrossRefGoogle Scholar
  20. 20.
    You, H., Yu, W., Munoz-Medellin, D., Brown, P. H., Sanders, B. G., and Kline, K. (2002) Role of extracellular signal-regulated kinase pathway in RRR-alpha-tocopheryl succinate-induced differentiation of human MDA-MB435 breast cancer cells, Mol. Carcinog., 33, 228–236.PubMedCrossRefGoogle Scholar
  21. 21.
    Swettenham, E., Witting, P. K., Salvatore, B. A., and Neuzil, J. (2005) Alpha-tocopheryl succinate selectively induces apoptosis in neuroblastoma cells: potential therapy of malignancies of the nervous system? J. Neurochem., 94, 1448–1456.PubMedCrossRefGoogle Scholar
  22. 22.
    Kang, T. H., Knoff, J., Yeh, W. H., Yang, B., Wang, C., Kim, Y. S., Kim, T. W., Wu, T. C., and Hung, C. F. (2014) Treatment of tumors with vitamin E suppresses myeloid derived suppressor cells and enhances CD8+ T-cell-mediated antitumor effects, PLoS One, 9, e103562.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Malafa, M. P., Fokum, F. D., Smith, L., and Louis, A. (2002) Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate, Ann. Surg. Oncol., 9, 1023–1032.PubMedCrossRefGoogle Scholar
  24. 24.
    Dong, L. F., Swettenham, E., Eliasson, J., Wang, X. F., Gold, M., Medunic, Y., Stantic, M., Low, P., Prochazka, L., Witting, P. K., Turanek, J., Akporiaye, E. T., Ralph, S. J., and Neuzil, J. (2007) Vitamin E analogues inhibit angiogenesis by selective induction of apoptosis in proliferating endothelial cells: the role of oxidative stress, Cancer Res., 67, 11906–11913.PubMedCrossRefGoogle Scholar
  25. 25.
    Behery, F. A., Elnagar, A. Y., Akl, M. R., Wali, V. B., Abuasal, B., Kaddoumi, A., Sylvester, P. W., and El Sayed, K. A. (2010) Redox-silent tocotrienol esters as breast cancer proliferation and migration inhibitors, Bioorg. Med. Chem., 18, 8066–8075.PubMedCrossRefGoogle Scholar
  26. 26.
    Chinery, R., Brockman, J. A., Peeler, M. O., Shyr, Y., Beauchamp, R. D., and Coffey, R. J. (1997) Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPbeta, Nat. Med., 3, 1233–1241.PubMedCrossRefGoogle Scholar
  27. 27.
    Lee, D., Shim, M. S., Kim, K. Y., Noh, Y. H., Kim, H., Kim, S. Y., Weinreb, R. N., and Ju, W. K. (2014) Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma, Invest. Ophthalmol. Vis. Sci., 55, 993–1005.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Diaz, Z., Colombo, M., Mann, K. K., Su, H., Smith, K. N., Bohle, D. S., Schipper, H. M., and Miller, W. H., Jr. (2005) Trolox selectively enhances arsenic-mediated oxidative stress and apoptosis in APL and other malignant cell lines, Blood, 105, 1237–1245.PubMedCrossRefGoogle Scholar
  29. 29.
    Nikolic, K. M. (2008) Design and QSAR study of analogs of alpha-tocopherol with enhanced antiproliferative activity against human breast adenocarcinoma cells, J. Mol. Graph. Model., 26, 137–143.CrossRefGoogle Scholar
  30. 30.
    Fariss, M. W., Fortuna, M. B., Everett, C. K., Smith, J. D., Trent, D. F., and Djuric, Z. (1994) The selective antiproliferative effects of alpha-tocopheryl hemisuccinate and cholesteryl hemisuccinate on murine leukemia cells result from the action of the intact compounds, Cancer Res., 54, 3346–3351.PubMedGoogle Scholar
  31. 31.
    Prasad, K. N., and Edwards-Prasad, J. (1982) Effects of tocopherol (vitamin E) acid succinate on morphological alterations and growth inhibition in melanoma cells in culture, Cancer Res., 42, 550–555.PubMedGoogle Scholar
  32. 32.
    Turley, J. M., Funakoshi, S., Ruscetti, F. W., Kasper, J., Murphy, W. J., Longo, D. L., and Birchenall-Roberts, M. C. (1995) Growth inhibition and apoptosis of RL human B lymphoma cells by vitamin E succinate and retinoic acid: role for transforming growth factor beta, Cell Growth Differ., 6, 655–663.PubMedGoogle Scholar
  33. 33.
    Turley, J. M., Fu, T., Ruscetti, F. W., Mikovits, J. A., Bertolette, D. C., 3rd, and Birchenall-Roberts, M. C. (1997) Vitamin E succinate induces Fas-mediated apoptosis in estrogen receptor-negative human breast cancer cells, Cancer Res., 57, 881–890.PubMedGoogle Scholar
  34. 34.
    Zhao, B., Yu, W., Qian, M., Simmons-Menchaca, M., Brown, P., Birrer, M. J., Sanders, B. G., and Kline, K. (1997) Involvement of activator protein-1 (AP-1) in induction of apoptosis by vitamin E succinate in human breast cancer cells, Mol. Carcinog., 19, 180–190.PubMedCrossRefGoogle Scholar
  35. 35.
    Neuzil, J., Weber, T., Terman, A., Weber, C., and Brunk, U. T. (2001) Vitamin E analogues as inducers of apoptosis: implications for their potential antineoplastic role, Redox Rep., 6, 143–151.PubMedCrossRefGoogle Scholar
  36. 36.
    Anderson, K., Simmons-Menchaca, M., Lawson, K. A., Atkinson, J., Sanders, B. G., and Kline, K. (2004) Differential response of human ovarian cancer cells to induction of apoptosis by vitamin E succinate and vitamin E analogue, alpha-TEA, Cancer Res., 64, 4263–4269.PubMedCrossRefGoogle Scholar
  37. 37.
    Shiau, C. W., Huang, J. W., Wang, D. S., Weng, J. R., Yang, C. C., Lin, C. H., Li, C., and Chen, C. S. (2006) aTocopheryl succinate induces apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 function, J. Biol. Chem., 281, 11819–11825.PubMedCrossRefGoogle Scholar
  38. 38.
    Huang, X., Li, L., Zhang, L., Zhang, Z., Wang, X., Zhang, X., Hou, L., and Wu, K. (2013) Crosstalk between endoplasmic reticulum stress and oxidative stress in apoptosis induced by a-tocopheryl succinate in human gastric carcinoma cells, Br. J. Nutr., 109, 727–735.PubMedCrossRefGoogle Scholar
  39. 39.
    Sun, Y., Zhao, Y., Hou, L., Zhang, X., Zhang, Z., and Wu, K. (2014) RRR-α-tocopheryl succinate induces apoptosis in human gastric cancer cells via the NF-κB signaling pathway, Oncol. Rep., 32, 1243–1248.PubMedGoogle Scholar
  40. 40.
    Stapelberg, M., Tomasetti, M., Alleva, R., Gellert, N., Procopio, A., and Neuzil, J. (2004) α-Tocopheryl succinate inhibits proliferation of mesothelioma cells by selective down-regulation of fibroblast growth factor receptors, Biochem. Biophys. Res. Commun., 318, 636–641.PubMedCrossRefGoogle Scholar
  41. 41.
    Alleva, R., Benassi, M. S., Tomasetti, M., Gellert, N., Ponticelli, F., Borghi, B., Picci, P., and Neuzil, J. (2005) Alpha-tocopheryl succinate induces cytostasis and apoptosis in osteosarcoma cells: the role of E2F1, Biochem. Biophys. Res. Commun., 331, 1515–1521.PubMedCrossRefGoogle Scholar
  42. 42.
    Neuzil, J., Dong, L. F., Wang, X. F., and Zingg, J. M. (2006) Tocopherol-associated protein-1 accelerates apoptosis induced by alpha-tocopheryl succinate in mesothelioma cells, Biochem. Biophys. Res. Commun., 343, 1113–1117.PubMedCrossRefGoogle Scholar
  43. 43.
    Yu, W., Israel, K., Liao, Q. Y., Aldaz, C. M., Sanders, B. G., and Kline, K. (1999) Vitamin E succinate (VES) induces Fas sensitivity in human breast cancer cells: role for Mr 43,000 Fas in VES-triggered apoptosis, Cancer Res., 59, 953–961.PubMedGoogle Scholar
  44. 44.
    Israel, K., Yu, W., Sanders, B. G., and Kline, K. (2000) Vitamin E succinate induces apoptosis in human prostate cancer cells: role for Fas in vitamin E succinate-triggered apoptosis, Nutr. Cancer, 36, 90–100.PubMedCrossRefGoogle Scholar
  45. 45.
    Neuzil, J., Weber, T., Gellert, N., and Weber, C. (2001) Selective cancer cell killing by alpha-tocopheryl succinate, Br. J. Cancer, 84, 87–89.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Zhao, Y., Neuzil, J., and Wu, K. (2009) Vitamin E analogues as mitochondria-targeting compounds: from the bench to the bedside? Mol. Nutr. Food Res., 53, 129–139.PubMedCrossRefGoogle Scholar
  47. 47.
    Kline, K., Yu, W., and Sanders, B. G. (2001) Vitamin E: mechanisms of action as tumor cell growth inhibitors, J. Nutr., 131, 161S–163S.PubMedGoogle Scholar
  48. 48.
    Wu, K., Zhao, Y., Liu, B. H., Li, Y., Liu, F., Guo, J., and Yu, W. P. (2002) RRR-alpha-tocopheryl succinate inhibits human gastric cancer SGC-7901 cell growth by inducing apoptosis and DNA synthesis arrest, World J. Gastroenterol., 8, 26–30.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Yu, W., Sanders, B. G., and Kline, K. (2003) RRR-alphatocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria, Cancer Res., 63, 2483–2491.PubMedGoogle Scholar
  50. 50.
    Weber, T., Dalen, H., Andera, L., Negre-Salvayre, A., Auge, N., Sticha, M., Lloret, A., Terman, A., Witting, P. K., Higuchi, M., Plasilova, M., Zivny, J., Gellert, N., Weber, C., and Neuzil, J. (2003) Mitochondria play a central role in apoptosis induced by alpha-tocopheryl succinate, an agent with antineoplastic activity: comparison with receptor-mediated pro-apoptotic signaling, Biochemistry, 42, 4277–4291.PubMedCrossRefGoogle Scholar
  51. 51.
    Wang, X. F., Witting, P. K., Salvatore, B. A., and Neuzil, J. (2005) Vitamin E analogs trigger apoptosis in HER2/erbB2-overexpressing breast cancer cells by signaling via the mitochondrial pathway, Biochem. Biophys. Res. Commun., 326, 282–289.PubMedCrossRefGoogle Scholar
  52. 52.
    Kogure, K., Hama, S., Manabe, S., Tokumura, A., and Fukuzawa, K. (2002) High cytotoxicity of alpha-tocopheryl hemisuccinate to cancer cells is due to failure of their antioxidative defense systems, Cancer Lett., 186, 151–156.PubMedCrossRefGoogle Scholar
  53. 53.
    Neuzil, J., Dyason, J. C., Freeman, R., Dong, L. F., Prochazka, L., Wang, X. F., Scheffler, I., and Ralph, S. J. (2007) Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II, J. Bioenerg. Biomembr., 39, 65–72.PubMedCrossRefGoogle Scholar
  54. 54.
    Dong, L. F., Low, P., Dyason, J. C., Wang, X. F., Prochazka, L., Witting, P. K., Freeman, R., Swettenham, E., Valis, K., Liu, J., Zobalova, R., Turanek, J., Spitz, D. R., Domann, F. E., Scheffler, I. E., Ralph, S. J., and Neuzil, J. (2008) Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II, Oncogene, 27, 4324–4335.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Prochazka, L., Dong, L. F., Valis, K., Freeman, R., Ralph, S. J., Turanek, J., and Neuzil, J. (2010) α-Tocopheryl succinate causes mitochondrial permeabilization by preferential formation of Bak channels, Apoptosis, 15, 782–794.PubMedCrossRefGoogle Scholar
  56. 56.
    Dos Santos, G. A., Abreue Lima, R. S., Pestana, C. R., Lima, A. S., Scheucher, P. S., Thome, C. H., GimenesTeixeira, H. L., Santana-Lemos, B. A., Lucena-Araujo, A. R., Rodrigues, F. P., Nasr, R., Uyemura, S. A., Falcao, R. P., De The, H., Pandolfi, P. P., Curti, C., and Rego, E. M. (2012) (+)a-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo, Leukemia, 26, 451–460.PubMedCrossRefGoogle Scholar
  57. 57.
    Rauchova, H., Vokurkova, M., and Drahota, Z. (2014) Inhibition of mitochondrial glycerol-3-phosphate dehydrogenase by a-tocopheryl succinate, Int. J. Biochem. Cell Biol., 53, 409–413.PubMedCrossRefGoogle Scholar
  58. 58.
    Gruber, J., Staniek, K., Krewenka, C., Moldzio, R., Patel, A., Bohmdorfer, S., Rosenau, T., and Gille, L. (2014) Tocopheramine succinate and tocopheryl succinate: mechanism of mitochondrial inhibition and superoxide radical production, Bioorg. Med. Chem., 22, 684–691.PubMedCrossRefGoogle Scholar
  59. 59.
    Alleva, R., Tomasetti, M., Andera, L., Gellert, N., Borghi, B., Weber, C., Murphy, M. P., and Neuzil, J. (2001) Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing mitochondrial antioxidant protection, FEBS Lett., 503, 46–50.PubMedCrossRefGoogle Scholar
  60. 60.
    Higuchi, M., Aggarwal, B. B., and Yeh, E. T. (1997) Activation of CPP32-like protease in tumor necrosis factor-induced apoptosis is dependent on mitochondrial function, J. Clin. Invest., 99, 1751–1758.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Kim, J. Y., Kim, Y. H., Chang, I., Kim, S., Pak, Y. K., Oh, B. H., Yagita, H., Jung, Y. K., Oh, Y. J., and Lee, M. S. (2002) Resistance of mitochondrial DNA-deficient cells to TRAIL: role of Bax in TRAIL-induced apoptosis, Oncogene, 21, 3139–3148.PubMedCrossRefGoogle Scholar
  62. 62.
    Savitskaya, M. A., and Onischenko, G. E. (2015) Mechanisms of apoptosis, Biochemistry (Moscow), 80, 1393–1405.CrossRefGoogle Scholar
  63. 63.
    Savitskaya, M. A., Vildanova, M. S., Kisurina-Evgenieva, O. P., Smirnova, E. A., and Onischenko, G. E. (2012) Mitochondrial pathway of a-tocopheryl succinate-induced apoptosis in human epidermoid carcinoma A431 cells, Acta Naturae, 4, 88–94.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Neuzil, J., Tomasetti, M., Zhao, Y., Dong, L. F., Birringer, M., Wang, X. F., Low, P., Wu, K., Salvatore, B. A., and Ralph, S. J. (2007) Vitamin E analogs, a novel group of “mitocans”, as anticancer agents: the importance of being redox-silent, Mol. Pharmacol., 71, 1185–1199.PubMedCrossRefGoogle Scholar
  65. 65.
    Ottino, P., and Duncan, J. R. (1997) Effect of alpha-tocopherol succinate on free radical and lipid peroxidation levels in BL6 melanoma cells, Free Radic. Biol. Med., 22, 1145–1151.PubMedCrossRefGoogle Scholar
  66. 66.
    Kang, Y. H., Lee, E., Choi, M. K., Ku, J. L., Kim, S. H., Park, Y. G., and Lim, S. J. (2004) Role of reactive oxygen species in the induction of apoptosis by alpha-tocopheryl succinate, Int. J. Cancer, 112, 385–392.PubMedCrossRefGoogle Scholar
  67. 67.
    Fukuzawa, K., Kogure, K., Morita, M., Hama, S., Manabe, S., and Tokumura, A. (2004) Enhancement of nitric oxide and superoxide generations by alpha-tocopheryl succinate and its apoptotic and anticancer effects, Biochemistry (Moscow), 69, 50–57.CrossRefGoogle Scholar
  68. 68.
    Stapelberg, M., Gellert, N., Swettenham, E., Tomasetti, M., Witting, P. K., Procopio, A., and Neuzil, J. (2005) Alpha-tocopheryl succinate inhibits malignant mesothelioma by disrupting the fibroblast growth factor autocrine loop: mechanism and the role of oxidative stress, J. Biol. Chem., 280, 25369–25376.PubMedCrossRefGoogle Scholar
  69. 69.
    Bellezza, I., Grottelli, S., Gatticchi, L., Mierla, A. L., and Minelli, A. (2014) a-Tocopheryl succinate pre-treatment attenuates quinone toxicity in prostate cancer PC3 cells, Gene, 539, 1–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Gogvadze, V., Norberg, E., Orrenius, S., and Zhivotovsky, B. (2010) Involvement of Ca2+ and ROS in alpha-tocopheryl succinate-induced mitochondrial permeabilization, Int. J. Cancer, 127, 1823–1832.PubMedCrossRefGoogle Scholar
  71. 71.
    Yamamoto, S., Tamai, H., Ishisaka, R., Kanno, T., Arita, K., Kobuchi, H., and Utsumi, K. (2000) Mechanism of alpha-tocopheryl succinate-induced apoptosis of promyelocytic leukemia cells, Free Radic. Res., 33, 407–418.PubMedCrossRefGoogle Scholar
  72. 72.
    Neuzil, J., Svensson, I., Weber, T., Weber, C., and Brunk, U. T. (1999) a-Tocopheryl succinate-induced apoptosis in Jurkat T-cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilization, FEBS Lett., 445, 295–300.PubMedCrossRefGoogle Scholar
  73. 73.
    Gu, X., Song, X., Dong, Y., Cai, H., Walters, E., Zhang, R., Pang, X., Xie, T., Guo, Y., Sridhar, R., and Califano, J. A. (2008) Vitamin E succinate induces ceramide-mediated apoptosis in head and neck squamous cell carcinoma in vitro and in vivo, Clin. Cancer Res., 14, 1840–1848.PubMedCrossRefGoogle Scholar
  74. 74.
    Becker, K. P., and Hannun, Y. A. (2005) Protein kinase C and phospholipase D: intimate interactions in intracellular signaling, Cell. Mol. Life Sci., 62, 1448–1461.PubMedCrossRefGoogle Scholar
  75. 75.
    Kim, S.-J., Park, J.-H., Lee, S.-R., Bag, O.-S., and Kang, S.-S. (2000) Activation of PKC-ßII is required for vitamin E-succinate-induced apoptosis of U937 cells, Korean J. Biol. Sci., 4, 279–285.CrossRefGoogle Scholar
  76. 76.
    Bang, O. S., Park, J. H., and Kang, S. S. (2001) Activation of PKC but not of ERK is required for vitamin E-succinateinduced apoptosis of HL-60 cells, Biochem. Biophys. Res. Commun., 288, 789–797.PubMedCrossRefGoogle Scholar
  77. 77.
    Cesen, M. H., Pegan, K., Spes, A., and Turk, B. (2012) Lysosomal pathways to cell death and their therapeutic applications, Exp. Cell Res., 318, 1245–1251.PubMedCrossRefGoogle Scholar
  78. 78.
    Conus, S., Pop, C., Snipas, S. J., Salvesen, G. S., and Simon, H. U. (2012) Cathepsin D primes caspase-8 activation by multiple intra-chain proteolysis, J. Biol. Chem., 287, 21142–21151.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Appelqvist, H., Waster, P., Eriksson, I., Rosdahl, I., and Ollinger, K. (2013) Lysosomal exocytosis and caspase-8mediated apoptosis in UVA-irradiated keratinocytes, J. Cell Sci., 126, 5578–5584.PubMedCrossRefGoogle Scholar
  80. 80.
    Roberg, K., Johansson, U., and Ollinger, K. (1999) Lysosomal release of cathepsin D precedes relocation of cytochrome c and loss of mitochondrial transmembrane potential during apoptosis induced by oxidative stress, Free Radic. Biol. Med., 27, 1228–1237.PubMedCrossRefGoogle Scholar
  81. 81.
    Wu, K., Zhao, L., Li, Y., Shan, Y. J., and Wu, L. J. (2004) Effects of vitamin E succinate on the expression of Fas and PCNA proteins in human gastric carcinoma cells and its clinical significance, World J. Gastroenterol., 10, 945–949.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Wu, K., Li, Y., Zhao, Y., Shan, Y. J., Xia, W., Yu, W. P., and Zhao, L. (2002) Roles of Fas signaling pathway in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells, World J. Gastroenterol., 8, 982–986.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Zhao, Y., Li, R., Xia, W., Neuzil, J., Lu, Y., Zhang, H., Zhao, X., Zhang, X., Sun, C., and Wu, K. (2010) Bid integrates intrinsic and extrinsic signaling in apoptosis induced by alpha-tocopheryl succinate in human gastric carcinoma cells, Cancer Lett., 288, 42–49.PubMedCrossRefGoogle Scholar
  84. 84.
    Tomasetti, M., Andera, L., Alleva, R., Borghi, B., Neuzil, J., and Procopio, A. (2006) α-Tocopheryl succinate induces DR4 and DR5 expression by a p53-dependent route: implication for sensitization of resistant cancer cells to TRAIL apoptosis, FEBS Lett., 580, 1925–1931.PubMedCrossRefGoogle Scholar
  85. 85.
    Weber, T., Lu, M., Andera, L., Lahm, H., Gellert, N., Fariss, M. W., Korinek, V., Sattler, W., Ucker, D. S., Terman, A., Schroder, A., Erl, W., Brunk, U. T., Coffey, R. J., Weber, C., and Neuzil, J. (2002) Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosisinducing ligand (Apo2 ligand) in vivo, Clin. Cancer Res., 8, 863–869.PubMedGoogle Scholar
  86. 86.
    Tomasetti, M., Rippo, M. R., Alleva, R., Moretti, S., Andera, L., Neuzil, J., and Procopio, A. (2004) Alphatocopheryl succinate and TRAIL selectively synergize in induction of apoptosis in human malignant mesothelioma cells, Br. J. Cancer, 90, 1644–1653.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Dalen, H., and Neuzil, J. (2003) Alpha-tocopheryl succinate sensitizes a T-lymphoma cell line to TRAIL-induced apoptosis by suppressing NF-kappaB activation, Br. J. Cancer, 88, 153–158.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Yu, W., Heim, K., Qian, M., Simmons-Menchaca, M., Sanders, B. G., and Kline, K. (1997) Evidence for role of transforming growth factor-beta in RRR-alpha-tocopheryl succinate-induced apoptosis of human MDA-MB-435 breast cancer cells, Nutr. Cancer, 27, 267–278.PubMedCrossRefGoogle Scholar
  89. 89.
    Charpentier, A., Groves, S., Simmons-Menchaca, M., Turley, J., Zhao, B., Sanders, B. G., and Kline, K. (1993) RRRalpha-tocopheryl succinate inhibits proliferation and enhances secretion of transforming growth factor-beta (TGFbeta) by human breast cancer cells, Nutr. Cancer, 19, 225–239.PubMedCrossRefGoogle Scholar
  90. 90.
    Charpentier, A., Simmons-Menchaca, M., Yu, W., Zhao, B., Qian, M., Heim, K., Sanders, B. G., and Kline, K. (1996) RRR-alpha-tocopheryl succinate enhances TGF-beta 1, -beta 2, and -beta 3 and TGF-beta R-II expression by human MDA-MB-435 breast cancer cells, Nutr. Cancer, 26, 237–250.PubMedCrossRefGoogle Scholar
  91. 91.
    Yu, W., Liao, Q. Y., Hantash, F. M., Sanders, B. G., and Kline, K. (2001) Activation of extracellular signal-regulated kinase and c-Jun-NH(2)-terminal kinase but not p38 mitogen-activated protein kinases is required for RRRalpha-tocopheryl succinate-induced apoptosis of human breast cancer cells, Cancer Res., 61, 6569–6576.PubMedGoogle Scholar
  92. 92.
    Wu, K., Liu, B. H., Zhao, D. Y., and Zhao, Y. (2001) Effect of vitamin E succinate on expression of TGF-beta1, c-Jun and JNK1 in human gastric cancer SGC-7901 cells, World J. Gastroenterol., 7, 83–87.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Bharti, A. C., and Aggarwal, B. B. (2002) Nuclear factorkappaB and cancer: its role in prevention and therapy, Biochem. Pharmacol., 64, 883–888.PubMedCrossRefGoogle Scholar
  94. 94.
    Wang, X. F., Xie, Y., Wang, H. G., Zhang, Y., Duan, X. C., and Lu, Z. J. (2010) α-Tocopheryl succinate induces apoptosis in erbB2-expressing breast cancer cell via NFκB pathway, Acta Pharmacol. Sin., 31, 1604–1610.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kanai, K., Kikuchi, E., Mikami, S., Suzuki, E., Uchida, Y., Kodaira, K., Miyajima, A., Ohigashi, T., Nakashima, J., and Oya, M. (2010) Vitamin E succinate induced apoptosis and enhanced chemosensitivity to paclitaxel in human bladder cancer cells in vitro and in vivo, Cancer Sci., 101, 216–223.PubMedCrossRefGoogle Scholar
  96. 96.
    Suzuki, Y. J., and Packer, L. (1993) Inhibition of NFkappaB DNA binding activity by alpha-tocopheryl succinate, Biochem. Mol. Biol. Int., 31, 693–700.PubMedGoogle Scholar
  97. 97.
    Erl, W., Weber, C., Wardemann, C., and Weber, P. C. (1997) α-Tocopheryl succinate inhibits monocytic cell adhesion to endothelial cells by suppressing NF-κB mobilization, Am. J. Physiol., 273, H634–H640.PubMedGoogle Scholar
  98. 98.
    Fang, J. Y., and Richardson, B. C. (2005) The MAPK signaling pathways and colorectal cancer, Lancet Oncol., 6, 322–327.PubMedCrossRefGoogle Scholar
  99. 99.
    Donapaty, S., Louis, S., Horvath, E., Kun, J., Sebti, S. M., and Malafa, M. P. (2006) RRR-alpha-tocopherol succinate down-regulates oncogenic Ras signaling, Mol. Cancer Ther., 5, 309–316.PubMedCrossRefGoogle Scholar
  100. 100.
    Prasad, K. N., Cohrs, R. J., and Sharma, O. K. (1990) Decreased expressions of c-myc and H-ras oncogenes in vitamin E succinate induced morphologically differentiated murine B-16 melanoma cells in culture, Biochem. Cell Biol., 68, 1250–1255.PubMedCrossRefGoogle Scholar
  101. 101.
    Cohrs, R. J., Torelli, S., Prasad, K. N., Edwards-Prasad, J., and Sharma, O. K. (1991) Effect of vitamin E succinate and a cAMP-stimulating agent on the expression of c-myc and N-myc and H-ras in murine neuroblastoma cells, Int. J. Dev. Neurosci., 9, 187–194.PubMedCrossRefGoogle Scholar
  102. 102.
    Lei, Y. Y., Wang, W. J., Mei, J. H., and Wang, C. L. (2014) Mitogen-activated protein kinase signal transduction in solid tumors, Asian Pac. J. Cancer Prev., 15, 8539–8548.PubMedCrossRefGoogle Scholar
  103. 103.
    Zu, K., Hawthorn, L., and Ip, C. (2005) Up-regulation of c-Jun-NH2-kinase pathway contributes to the induction of mitochondria-mediated apoptosis by alpha-tocopheryl succinate in human prostate cancer cells, Mol. Cancer Ther., 4, 43–50.PubMedCrossRefGoogle Scholar
  104. 104.
    Yu, W., Simmons-Menchaca, M., You, H., Brown, P., Birrer, M. J., Sanders, B. G., and Kline, K. (1998) RRRalpha-tocopheryl succinate induction of prolonged activation of c-jun amino-terminal kinase and c-jun during induction of apoptosis in human MDA-MB-435 breast cancer cells, Mol. Carcinog., 22, 247–257.PubMedCrossRefGoogle Scholar
  105. 105.
    Wu, K., Zhao, Y., Li, G. C., and Yu, W. P. (2004) c-Jun Nterminal kinase is required for vitamin E succinateinduced apoptosis in human gastric cancer cells, World J. Gastroenterol., 10, 1110–1114.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Zhao, Y., Wu, K., Xia, W., Shan, Y. J., Wu, L. J., and Yu, W. P. (2002) The effects of vitamin E succinate on the expression of c-jun gene and protein in human gastric cancer SGC-7901 cells, World J. Gastroenterol., 8, 782–786.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Zhao, Y., Zhao, X., Yang, B., Neuzil, J., and Wu, K. (2007) a-Tocopheryl succinate-induced apoptosis in human gastric cancer cells is modulated by ERK1/2 and c-Jun N-terminal kinase in a biphasic manner, Cancer Lett., 247, 345–352.PubMedCrossRefGoogle Scholar
  108. 108.
    Akazawa, A., Nishikawa, K., Suzuki, K., Asano, R., Kumadaki, I., Satoh, H., Hagiwara, K., Shin, S. J., and Yano, T. (2002) Induction of apoptosis in a human breast cancer cell overexpressing ErbB-2 receptor by alpha-tocopheryloxybutyric acid, Jpn. J. Pharmacol., 89, 417–421.PubMedCrossRefGoogle Scholar
  109. 109.
    Kim, S. J., Bang, O. S., Lee, Y. S., and Kang, S. S. (1998) Production of inducible nitric oxide is required for monocytic differentiation of U937 cells induced by vitamin Esuccinate, J. Cell Sci., 111, 435–441.PubMedGoogle Scholar
  110. 110.
    Prasad, K. N., Kentroti, S., Edwards-Prasad, J., Vernadakis, A., Imam, M., Carvalho, E., and Kumar, S. (1994) Modification of the expression of adenosine 3',5'cyclic monophosphate-induced differentiated functions in neuroblastoma cells by beta-carotene and D-alpha-tocopheryl succinate, J. Am. Coll. Nutr., 13, 298–303.PubMedCrossRefGoogle Scholar
  111. 111.
    Yu, W., Sanders, B. G., and Kline, K. (2002) RRR-alphatocopheryl succinate induction of DNA synthesis arrest of human MDA-MB-435 cells involves TGF-beta-independent activation of p21Waf1/Cip1, Nutr. Cancer, 43, 227–236.PubMedCrossRefGoogle Scholar
  112. 112.
    Turley, J. M., Ruscetti, F. W., Kim, S. J., Fu, T., Gou, F. V., and Birchenall-Roberts, M. C. (1997) Vitamin E succinate inhibits proliferation of BT-20 human breast cancer cells: increased binding of cyclin A negatively regulates E2F transactivation activity, Cancer Res., 57, 2668–2675.PubMedGoogle Scholar
  113. 113.
    Turley, J. M., Sanders, B. G., and Kline, K. (1992) RRRalpha-tocopheryl succinate modulation of human promyelocytic leukemia (HL-60) cell proliferation and differentiation, Nutr. Cancer, 18, 201–213.PubMedCrossRefGoogle Scholar
  114. 114.
    Prasad, K. C. (1989) Induction of differentiated phenotypes in melanoma cells by a combination of an adenosine 3',5'-cyclic monophosphate stimulating agent and Dalpha tocopheryl succinate, Cancer Lett., 44, 17–22.PubMedCrossRefGoogle Scholar
  115. 115.
    You, H., Yu, W., Sanders, B. G., and Kline, K. (2001) RRR-alpha-tocopheryl succinate induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo differentiation, Cell Growth Differ., 12, 471–480.PubMedGoogle Scholar
  116. 116.
    Yanamala, N., Kapralov, A. A., Djukic, M., Peterson, J., Mao, G., Klein-Seetharaman, J., Stoyanovsky, D. A., Stursa, J., Neuzil, J., and Kagan, V. E. (2014) Structural rearrangement and peroxidase activation of cytochrome c by anionic analogues of vitamin E, tocopherol succinate and tocopherol phosphate, J. Biol. Chem., 289, 32488–32498.PubMedPubMedCentralCrossRefGoogle Scholar

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© Pleiades Publishing, Ltd. 2016

Authors and Affiliations

  1. 1.Faculty of BiologyLomonosov Moscow State UniversityMoscowRussia

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