• 1
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 6990.
  • 2
    Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989; 244: 70712.
  • 3
    Zhou BP, Hung MC. Dysregulation of cellular signaling by HER2/neu in breast cancer. Semin Oncol 2003; 30: 3848.
  • 4
    Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-Akt pathway in human cancer. Nat Rev Cancer 2002; 2: 489501.
  • 5
    Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol 2001; 19: 258795.
  • 6
    Feldman AM, Lorell BH, Reis SE. Trastuzumab in the treatment of metastatic breast cancer: anticancer therapy versus cardiotoxicity. Circulation 2000; 102: 2724.
  • 7
    Keefe DL. Trastuzumab-associated cardiotoxicity. Cancer 2002; 95: 1592600.
  • 8
    Ralph SJ, Neuzil J. Mitochondria as targets for cancer therapy. In: Sing K, Costello L, eds. Mitochondria and Cancer. New York, NY: Springer Science, 2009. 211250.
  • 9
    Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 2009; 8: 57991.
  • 10
    Fulda S, Galluzzi L, Kroemer G. Targeting mitochondria for cancer therapy. Nat Rev Drug Discov 2010; 9: 44764.
  • 11
    Neuzil J, Weber T, Schröder A, Lu M, Ostermann G, Gellert N, Mayne GC, Olejnicka B, Nègre-Salvayre A, Sticha M, Coffey RJ, Weber C. Induction of apoptosis in cancer cells by α-tocopheryl succinate: molecular pathways and structural requirements. FASEB J 2001; 15: 40315.
  • 12
    Zhang Y, Ni J, Messing EM, Chang E, Yang CR, Yeh S. Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells. Proc Natl Acad Sci USA 2002; 99: 740813.
  • 13
    Kline K, Yu W, Sanders BG. Vitamin E and breast cancer. J Nutr 2004; 134: 3458S62S.
  • 14
    Shiau CW, Huang JW, Wang DS, Weng JR, Yang CC, Lin CH, Li C, Chen CS. Tocopheryl succinate induces apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 function. J Biol Chem 2006; 281: 1181925.
  • 15
    Neuzil J, Dong LF, Ramanathapuram L, Hahn T, Chladova M, Wang XF, Zobalova R, Prochazka L, Gold M, Freeman RE, Turanek J, Akporiaye ET, et al. Vitamin E analogues: a novel group of mitocans, anti-cancer agents that act by targeting mitochondria. Mol Aspects Med 2007; 28: 60745.
  • 16
    Neuzil J, Tomasetti M, Zhao Y, Dong LF, Birringer M, Wang XF, Low P, Wu K, Salvatore BA, Ralph SJ. Vitamin E analogs, a novel group of ‘mitocans’, as anti-cancer agents: the importance of being redox-silent. Mol Pharmacol 2007; 71: 118599.
  • 17
    Wang XF, Witting PK, Salvatore BA, Neuzil J. α-Tocopheryl succinate induces apoptosis in HER2/erbB2-overexpressing breast cancer cells by signalling via the mitochondrial pathway. Biochem Biophys Res Commun 2005; 326: 2829.
  • 18
    Wang XF, Birringer M, Dong LF, Veprek P, Low P, Swettenham E, Stantic M, Yuan LH, Zobalova R, Wu K, Ralph SJ, Ledvina M, Neuzil J. A peptide adduct of vitamin E succinate targets breast cancer cells with high erbB2 expression. Cancer Res 2007; 67: 333744.
  • 19
    Neuzil J, Massa H. Hepatic processing determines dual activity of vitamin E succinate. Biochem Biophys Res Commun 2005; 327: 10247.
  • 20
    Lawson KA, Anderson K, Menchaca M, Atkinson J, Sun L, Knight V, Gilbert BE, Conti C, Sanders BG, Kline K. Novel vitamin E analogue decreases syngeneic mouse mammary tumor burden and reduces lung metastases. Mol Cancer Ther 2003; 2: 43744.
  • 21
    Hahn T, Szabo TL, Gold M, Ramanathapuram L, Hurley LH, Akporiaye ET. Dietary administration of the pro-apoptotic vitamin E analogue α-tocopheryloxyacetic acid inhibits metastatic murine breast cancer. Cancer Res 2006; 66: 93748.
  • 22
    Hahn T, Fried K, Hurley LH, Akporiaye ET. Orally active α-tocopheryloxyacetic acid suppresses tumor growth and multiplicity of spontaneous murine breast cancer. Mol Cancer Ther 2009; 8: 15708.
  • 23
    Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 1992; 89: 1057882.
  • 24
    Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells 1998; 16: 41328.
  • 25
    Neuzil J, Wang XF, Dong LF, Low P, Ralph SJ. Molecular mechanism of ‘mitocan’-induced apoptosis in cancer cells epitomizes the multiple roles of reactive oxygen species and Bcl-2 family proteins. FEBS Lett 2006; 580: 51259.
  • 26
    Wilhelm K. Determination of human plasma cholinesterase activity by adapted Ellman's method. Arh Hig Rada Toksikol 1968; 19: 199207.
  • 27
    Shou J, Massarsweh S, Osborne CK, Wakelong AE, Ali S, Schiff R. Mechanism of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 2004; 96: 92635.
  • 28
    Weber T, Dalen H, Andera L, Nègre-Salvayre A, Augé N, Sticha M, Loret A, Terman A, Witting PK, Higuchi M, Plasilova M, Zivny J, et al. Mitochondria play a central role in apoptosis induced by α-tocopheryl succinate, an agent with anticancer activity. Comparison with receptor-mediated pro-apoptotic signaling. Biochemistry 2003; 42: 427791.
  • 29
    Neuzil J, Cerny J, Dyason JC, Dong LF, Ralph SJ. Affinity of vitamin E analogues for the ubiquinone site in the mitochondrial complex II correlates with their apoptotic activity. Mol Nutr Food Res 2011;55:154351.
  • 30
    Dong LF, Swettenham E, Eliasson J, Wang XF, Gold M, Medunic Y, Stantic M, Low P, Prochazka L, Witting PK, Turanek J, Akporiaye ET, et al. Vitamin E analogs inhibit angiogenesis by selective apoptosis induction in proliferating endothelial cells: the role of oxidative stress. Cancer Res 2007; 67: 1190613.
  • 31
    Dong LF, Low P, Dyason J, Wang XF, Prochazka L, Witting PK, Freeman R, Swettenham E, Valis K, Liu J, Zobalova R, Turanek J, et al. α-Tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene 2008; 27: 432435.
  • 32
    Dong LF, Freeman R, Liu J, Zobalova R, Marin-Hernandez A, Stantic M, Rohlena J, Rodriguez-Enriquez S, Valis K, Butcher B, Goodwin J, Brunk UT, et al. Suppression of tumour growth in vivo by the mitocan α-tocopheryl succinate requires respiratory complex II. Clin Cancer Res 2009; 15: 1593600.
  • 33
    Dong LF, Jameson VJA, Tilly D, Cerny J, Mahdavian E, Marín-Hernández A, Hernández-Esquivel L, Rodríguez-Enríquez S, Stursa J, Witting PK, Stantic B, Rohlena J, et al. Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II. J Biol Chem 2011; 286: 37178.
  • 34
    Gottlieb E, Tomlinson IP. Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 2005; 5: 85766.
  • 35
    Schiavi F, Schiavi F, Boedeker CC, Bausch B, Peczkowska M, Gomez CF, Strassburg T, Pawlu C, Buchta M, Salzmann M, Hoffmann MM, Berlis A, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. J Am Med Assoc 2005; 294: 205763.
  • 36
    Peczkowska M, Cascon A, Prejbisz A, Kubaszek A, Cwikła BJ, Furmanek M, Erlic Z, Eng C, Januszewicz A, Neumann HP. Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation. Nat Clin Pract Endocrinol Metab 2008; 4: 1115.
  • 37
    Fariss MW, Furtuna MB, Everett CK, Smith JD, Trent DF, Djuric Z. The selective antiproliferative effects of α-tocopheryl hemisuccinate and cholesteryl hemisuccinate on murine leukemia cells result from the action of the intact compound. Cancer Res 1994; 54: 334651.
  • 38
    Stapelberg M, Gellert N, Swettenham E, Tomasetti M, Witting PK, Procopio A, Neuzil J. α-Tocopheryl succinate inhibits malignant mesothelioma by disrupting the FGF autocrine loop: the role of oxidative stress. J Biol Chem 2005; 280: 2536976.
  • 39
    Valis K, Prochazka L, Boura E, Chladova M, Obsil T, Rohlena J, Truksa J, Dong LF, Ralph SJ, Neuzil J. Hippo/Mst1 stimulates transcription of NOXA in a FoxO1-dependent manner. Cancer Res 2011; 71: 94654.
  • 40
    Dong LF, Jameson VJA, Tilly D, Prochazka L, Rohlena J, Valis K, Truksa J, Zobalova R, Mahdavian E, Kluckova K, Stantic M, Stursa J, et al. Mitochondrial targeting of α-tocopheryl succinate enhances its pro-apoptotic efficacy: a new paradigm of efficient anti-cancer therapy. Free Radic Biol Med 2011; 50: 154655.
  • 41
    Prochazka L, Dong LF, Valis K, Freeman R, Ralph SJ, Turanek J, Neuzil J. α-Tocopheryl succinate causes mitochondrial permeabilization by preferential formation of Bak channel. Apoptosis 2010; 15: 78294.
  • 42
    Traber MG. Vitamin E regulatory mechanisms. Annu Rev Nutr 2007; 27: 34762.
  • 43
    Wechter WJ, Kantoci D, Murray ED Jr, D'Amico DC, Jung ME, Wang WH. A new endogenous natriuretic factor: LLU-α. Proc Natl Acad Sci USA 1996; 93: 60027.
  • 44
    Birringer M, Drogan D, Brigelius-Flohe R. Tocopherols are metabolized in HepG2 cells by side chain ω-oxidation and consecutive β-oxidation. Free Radic Biol Med 2001; 31: 22632.
  • 45
    Anderson K, Simmons-Menchaca M, Lawson KA, Atkinson J, Sanders BG, Kline K. Differential response of human ovarian cancer cells to induction of apoptosis by vitamin E succinate and vitamin E analogue, α-TEA. Cancer Res 2004; 64: 42639.
  • 46
    Weber T, Lu M, Andera L, Lahm H, Gellert N, Fariss MW, Korinek V, Sattler W, Ucker DS, Terman A, Schröder A, Erl W, et al. Vitamin E succinate is a potent novel anti-neoplastic agent with high tumor selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L) in vivo. Clin Cancer Res 2002; 8: 8639.