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Tocotrienols in the Control of Pathological Fibroinflammatory Processes

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Natural compounds as inducers of cell death

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Abstract

Chronic pancreatitis, liver cirrhosis or inflammatory bowel disease are examples of fibroinflammatory conditions, all of them characterized by a progressive course and poor therapeutic expectations. The signature of these disorders is the perpetual activation of myofibroblasts and the accumulation of redundant fibrotic tissue that progressively replaces the normal parenchyma. Removal of myofibroblast is increasingly recognized as a therapeutic target for the prevention and resolution of fibrosis. Tocotrienols are natural vitamin E compounds with potent anticancer properties. Their antineoplastic credentials are supported by the ability to selectively induce cell death or inhibit proliferation in transformed cells. Recent studies have shown that tocotrienols also strike activated fibroblasts without harming normal cells. This review focus on the current knowledge of the putative role of tocotrienols as antiinflammatory and antifibrogenic agents based on their ability to induce programmed cell death in activated fibroblasts. The review points out to the mitochondria as the main target of tocotrienols to promote apoptosis and autophagy in activated fibroblasts. Most of the available evidence has been gathered using experimental data from pancreatic stellate cells. The overall experimental evidence provides support to consider evaluating clinical trials using tocotrienols to reduce or prevent fibrosis in human fibroinflammatory diseases.

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References

  • Agarwal MK, Agarwal ML, Athar M, Gupta S (2004) Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association. Cell Cycle 3:205–211

    Article  PubMed  CAS  Google Scholar 

  • Aggarwal BB, Sundarama C, Prasada S, Kannappana R (2010a) Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol 80:1613–1631

    Article  PubMed  CAS  Google Scholar 

  • Aggarwal BB, Sundaram C, Prasad S, Kannappan R (2010b) Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol 80:1613–1631

    Article  PubMed  CAS  Google Scholar 

  • Ahn KS, Sethi G, Krishnan K, Aggarwal BB (2007) Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. J Biol Chem 282:809–820

    Article  PubMed  CAS  Google Scholar 

  • Behery FA, Elnagar AY, Akl MR, Wali VB, Abuasal B, Kaddoumi A, Sylvester PW, El Sayed KA (2010) Redox-silent tocotrienol esters as breast cancer proliferation and migration inhibitors. Bioorg Med Chem 18(22):8066–8075

    Article  PubMed  CAS  Google Scholar 

  • Birringer M, EyTina JH, Salvatore BA, Neuzil J (2003) Vitamin E analogues as inducers of apoptosis: structure–function relation. Br J Cancer 88:1948–1955

    Article  PubMed  CAS  Google Scholar 

  • Constantinou C, Papas A, Constantinou AI (2008) Vitamin E and cancer: an insight into the anticancer activities of vitamin E isomers and analogs. Int J Cancer 123:739–752

    Article  PubMed  CAS  Google Scholar 

  • Dong LF, Low P, Dyason JC, Wang XF, Prochazka L, Witting PK, Freeman R, Swettenham E, Valis K, Liu J, Zobalova R, Turanek J, Spitz DR, Domann FE, Scheffler IE, Ralph SJ, Neuzil J (2008) Alpha-tocopheryl succinate induces apoptosis by targeting ubiquinone-binding sites in mitochondrial respiratory complex II. Oncogene 27:4324–4335

    Article  PubMed  CAS  Google Scholar 

  • Elmore SP, Qian T, Grissom SF, Lemasters JJ (2001) The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J 15:2286–2287

    PubMed  CAS  Google Scholar 

  • Elsharkawy AM, Oakley F, Mann DA (2005) The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 5:927–939

    Article  Google Scholar 

  • Elson CE (1992) Tropical oils: nutritional and scientific issues. Crit Rev Food Sci Nutr 31:79–102

    Article  PubMed  CAS  Google Scholar 

  • Friedman SL (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125–172

    Article  PubMed  CAS  Google Scholar 

  • Fulda S, Galluzzi L, Kroemer G (2010) Targeting mitochondria for cancer therapy. Nat Rev Drug Discov 9:447–464

    Article  PubMed  CAS  Google Scholar 

  • Gogvadze V, Orrenius S, Zhivotovsky B (2008) Mitochondria in cancer cells: what is so special about them? Trends Cell Biol 18:165–173

    Article  PubMed  CAS  Google Scholar 

  • Hussein D, Mo H (2009) d-Dlta-tocotrienol-mediated suppression of the proliferation of human PANC-1, MIA PaCa-2, and BxPC-3 pancreatic carcinoma cells. Pancreas 38:124–136

    Article  Google Scholar 

  • Kaileh M, Sen R (2010) Role of NF-kappaB in the anti-inflammatory effects of tocotrienols. J Am Coll Nutr 29(3 Suppl):334S–339S

    PubMed  CAS  Google Scholar 

  • Kamal-Eldin A, Appelqvist LA (1996) The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids 31:671–701

    Article  PubMed  CAS  Google Scholar 

  • Khosla P, Patel V, Whinter JM, Khanna S, Rakhkovskaya M, Roy S, Sen CK (2006) Postprandial levels of the natural vitamin E tocotrienol in human circulation. Antioxid Redox Signal 8:1059–1068

    Article  PubMed  CAS  Google Scholar 

  • Kim EH, Sohn S, Kwon HJ, Kim SU, Kim MJ, Lee SJ, Choi KS (2007) Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. Cancer Res 67:6314–6324

    Article  PubMed  CAS  Google Scholar 

  • Kroemer G, Pouyssegur J (2008) Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell 13:472–482

    Article  PubMed  CAS  Google Scholar 

  • Kuhad A, Chopra K (2009) Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. Neuropharmacology 57:456–462

    Article  PubMed  CAS  Google Scholar 

  • Luna J, Masamunt MC, Rickmann M, Mora R, España C, Delgado S, Llach J, Vaquero E, Sans M (2011) Tocotrienols have potent antifibrogenic effects in human intestinal fibroblasts. Inflamm Bowel Dis 17(3):732–741

    Article  Google Scholar 

  • Modica-Napolitano JS, Singh KK (2004) Mitochondrial dysfunction in cancer. Mitochondrion 4:755–762

    Article  PubMed  CAS  Google Scholar 

  • Moretti L, Yang ES, Kim KW, Lu B (2007) Autophagy signaling in cancer and its potential as novel target to improve anticancer therapy. Drug Resist Updat 10:135–143

    Article  PubMed  CAS  Google Scholar 

  • Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ (2001) Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration. J Pharmacol Exp Ther 299:638–644

    PubMed  CAS  Google Scholar 

  • Neuzil J (2003) Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity. Br J Cancer 89:1822–1826

    Article  PubMed  CAS  Google Scholar 

  • Novo E, di Bonzo LV, Cannito S, Colombatto S, Parola M (2009) Hepatic myofibroblasts: a heterogeneous population of multifunctional cells in liver fibrogenesis. Int J Biochem Cell Biol 41:2089–2093

    Article  PubMed  CAS  Google Scholar 

  • Oakley F, Meso M, Iredale JP, Green K, Marek CJ, Zhou X, May MJ, Millward-Sadler H, Wright MC, Mann DA (2005) Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 128:108–120

    Article  PubMed  CAS  Google Scholar 

  • Omary MB, Lugea A, Lowe AW, Pandol SJ (2007) The pancreatic stellate cell: a star on the rise in pancreatic diseases. J Clin Invest 117:50–59

    Article  PubMed  CAS  Google Scholar 

  • Park SK, Sanders BG, Kline K (2010) Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling. Breast Cancer Res Treat 124:361–375

    Article  PubMed  CAS  Google Scholar 

  • Patel V, Khanna S, Roy S, Ezziddin O, Sen CK (2006) Natural vitamin E alpha-tocotrienol: retention in vital organs in response to long-term oral supplementation and withdrawal. Free Radic Res 40:763–771

    Article  PubMed  CAS  Google Scholar 

  • Ramachandran P, Iredale JP (2009) Reversibility of liver fibrosis. Ann Hepatol 8:283–291

    PubMed  Google Scholar 

  • Rickmann M, Vaquero EC, Malagelada JR, Molero X (2007) Tocotrienols induce apoptosis and autophagy in rat pancreatic stellate cells through the mitochondrial death pathway. Gastroenterology 132:2518–2532

    Article  PubMed  CAS  Google Scholar 

  • Sakai M, Okabe M, Tachibana H, Yamada K (2006) Apoptosis induction by gamma-tocotrienol in human hepatoma Hep3B cells. J Nutr Biochem 7:672–676

    Article  Google Scholar 

  • Sen CK, Khanna S, Rink C, Roy S (2007) Tocotrienols: the emerging face of natural vitamin E. Vitam Horm 76:203–261

    Article  PubMed  CAS  Google Scholar 

  • Serbinova EA, Packer L (1994) Antioxidant properties of alpha-tocopherol and alpha-tocotrienol. Methods Enzymol 234:354–366

    Article  PubMed  CAS  Google Scholar 

  • Shibata A, Nakagawa K, Kawakami Y, Tsuzuki T, Miyazawa T (2010) Suppression of gamma-tocotrienol on UVB induced inflammation in HaCaT keratinocytes and HR-1 hairless mice via inflammatory mediators multiple signaling. J Agric Food Chem 58:7013–7020

    Article  PubMed  CAS  Google Scholar 

  • Srivastava JK, Gupta S (2006) Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells. Biochem Biophys Res Commun 346:447–453

    Article  PubMed  CAS  Google Scholar 

  • Sun W, Xu W, Liu H, Liu J, Wang Q, Zhou J, Dong F, Chen B (2009) Gamma-tocotrienol induces mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem 20:276–284

    Article  PubMed  CAS  Google Scholar 

  • Suzuki YJ, Tsuchiya M, Wassall SR, Choo YM, Govil G, Kagan VE, Packer L (1993) Structural and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: implication to the molecular mechanism of their antioxidant potency. Biochemistry 32:10692–10699

    Article  PubMed  CAS  Google Scholar 

  • Takahashi K, Loo G (2004) Disruption of mitochondria during tocotrienol-induced apoptosis in MDA-MB-231 human breast cancer cells. Biochem Pharmacol 67:315–324

    Article  PubMed  CAS  Google Scholar 

  • Tappeiner C, Meyenberg A, Goldblum D, Mojon D, Zingg JM, Nesaretnam K, Kilchenmann M, Frueh BE (2010) Antifibrotic effects of tocotrienols on human Tenon’s fibroblasts. Graefes Arch Clin Exp Ophthalmol 248:65–71

    Article  PubMed  CAS  Google Scholar 

  • Theriault A, Chao JT, Gapor A (2002) Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes. Atherosclerosis 160:21–30

    Article  PubMed  CAS  Google Scholar 

  • Turcotte S, Giaccia AJ (2010) Targeting cancer cells through autophagy for anticancer therapy. Curr Opin Cell Biol 22:246–251

    Article  PubMed  CAS  Google Scholar 

  • Wali VB, Bachawal SV, Sylvester PW (2009a) Combined treatment of gamma-tocotrienol with statins induce mammary tumor cell cycle arrest in G1. Exp Biol Med 234:639–650

    Article  CAS  Google Scholar 

  • Wali VB, Bachawal SV, Sylvester PW (2009b) Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells. Apoptosis 14:1366–1377

    Article  PubMed  CAS  Google Scholar 

  • Wu SJ, Liu PL, Ng LT (2008) Tocotrienol-rich fraction of palm oil exhibits anti-inflammatory property by suppressing the expression of inflammatory mediators in human monocytic cells. Mol Nutr Food Res 52:921–929

    Article  PubMed  CAS  Google Scholar 

  • Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199–210

    Article  PubMed  CAS  Google Scholar 

  • Yam ML, Abdul Hafid SR, Cheng HM, Nesaretnam K (2009) Tocotrienols suppress proinflammatory markers and cyclooxygenase-2 expression in RAW264.7 Macrophages. Lipids 44:787–797

    Article  PubMed  CAS  Google Scholar 

  • Yang Z, Klionsky DJ (2010) Eaten alive: a history of macroautophagy. Nat Cell Biol 12:814–822

    Article  PubMed  CAS  Google Scholar 

  • Yang Z, Xiao H, Jin H, Koo PT, Tsang DJ, Yang CS (2010) Synergistic actions of atorvastatin with gamma-tocotrienol and celecoxib against human colon cancer HT29 and HCT116 cells. Int J Cancer 126:852–863

    PubMed  CAS  Google Scholar 

  • Yap SP, Yuen KH (2004) Influence of lipolysis and droplet size on tocotrienol absorption from self-emulsifying formulations. Int J Pharm 281:67–78

    Article  PubMed  CAS  Google Scholar 

  • Yap SP, Yuen KH, Wong JW (2001) Pharmacokinetics and bioavailability of α-, γ- and δ-tocotrienols under different food status. J Pharm Pharmacol 53:67–71

    Article  PubMed  CAS  Google Scholar 

  • Yap WN, Chang PN, Han HY, Lee DT, Ling MT, Wong YC, Yap YL (2008) Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. Br J Cancer 99:1832–1841

    Article  PubMed  CAS  Google Scholar 

  • Yoshida Y, Niki E, Noguchi N (2003) Comparative study on the action of tocopherols and tocotrienols as antioxidant: chemical and physical effects. Chem Phys Lipids 123:63–75

    Article  PubMed  CAS  Google Scholar 

  • Zhao Y, Neuzil J, Wu K (2009) Vitamin E analogues as mitochondria-targeting compounds: from the bench to the bedside? Mol Nutr Food Res 53:129–139

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Gastrointestinal and Pancreatic Research Group, Hospital Clínic, CIBEREHD, Barcelona, Spain

    Eva C. Vaquero

  2. Pancreatic Research Group, Institut de Recerca, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    Xavier Molero

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  1. Eva C. Vaquero
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  2. Xavier Molero
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Correspondence to Eva C. Vaquero .

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Editors and Affiliations

  1. , Laboratoire de Biologie Moléculaire et C, Hôpotal Kirchberg, Rue Edward Steichen 9, Steichen, L- 2540, Luxembourg

    Marc Diederich

  2. , Laboratoire de Biologie Moléculaire et C, Hôpotal Kirchberg, Rue Edward Steichen 9, Steichen, L- 2540, Luxembourg

    Karoline Noworyta

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Vaquero, E.C., Molero, X. (2012). Tocotrienols in the Control of Pathological Fibroinflammatory Processes. In: Diederich, M., Noworyta, K. (eds) Natural compounds as inducers of cell death. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4575-9_20

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