Pharmacological potential of tocotrienols: A review

Nutrition and Metabolism

Volumn 11, Issue 1, 2014, Pages

  Ahsan, Haseeb ^a   Ahad, Amjid ^b   Iqbal, Jahangir ^c   Siddiqui, Waseem A ^b  

^a JAMIA MILLIA ISLAMIA CENTRAL UNIVERSITY   (India)

^b HAMDARD UNIVERSITY   (India)

^c SUNY DOWNSTATE MEDICAL CENTER   (United States)

Author keywords

Anti cancer; Anti inflammatory; Antioxidant; Cardioprotective; Dietary tocotrienols; Hypoglycaemic; Hypolipidemic; Pharmacology

Indexed keywords

ALPHA TOCOPHEROL; ALPHA TOCOTRIENOL; GEMCITABINE; INSULIN; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 1; PALM OIL; PENTOXIFYLLINE; PLACEBO; REACTIVE NITROGEN SPECIES; SELENIUM; TAMOXIFEN; TETANUS TOXOID;

ADJUVANT THERAPY; ALCOHOLISM; ANTIDIABETIC ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; BONE METABOLISM; BREAST CANCER; CANCER PREVENTION; CANCER SPECIFIC SURVIVAL; CARDIOVASCULAR DISEASE; DIABETIC NEPHROPATHY; DIABETIC NEUROPATHY; DIET SUPPLEMENTATION; DRUG ACCUMULATION; DRUG BLOOD LEVEL; DRUG METABOLISM; DRUG PENETRATION; DRUG SAFETY; DRUG STRUCTURE; EXPERIMENTAL MAMMARY NEOPLASM; HEART PROTECTION; HUMAN; HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIA; IMMUNOMODULATION; IMMUNOSTIMULATION; INTERMITTENT CLAUDICATION; LIVER PROTECTION; LIVER TOXICITY; NEUROPROTECTION; NONHUMAN; PANCREAS CANCER; PROSTATE CANCER; RADIATION INJURY; RADIATION PROTECTION; RECURRENCE FREE SURVIVAL; RENAL PROTECTION; REVIEW; STOMACH PROTECTION; STREPTOZOTOCIN-INDUCED DIABETES MELLITUS;

EID: 84988429208     PISSN: None     EISSN: 17437075     Source Type: Journal    
DOI: 10.1186/1743-7075-11-52     Document Type: Review

References (226)

1. Evans HM, Bishop KS: On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science 1922, 56:650-651.
2. Evans HM, Emerson OH, Emerson GA: The isolation from wheat germ oil of an alcohol, a-tocopherol, having the properties of vitamin E. J Biol Chem 1936, 113(1):319-332.
3. Whittle KJ, Dunphy PJ, Pennock JF: The isolation and properties of delta-tocotrienol from Hevea latex. Biochem J 1966, 100(1):138-145.
4. Qureshi AA, Burger WC, Peterson DM, Elson CE: The structure of an inhibitor of cholesterol biosynthesis isolated from barley. J Biol Chem 1986, 261(23):10544-10550.
5. Guthrie N, Gapor A, Chambers AF, Carroll KK: Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and-positive MCF-7 human breast cancer cells by palm oil tocotrienols and tamoxifen, alone and in combination. J Nutr 1997, 127(3):544S-548S.
6. Kato A, Gapor A, Tanabe K, Yamaoka M, Mamuro H: Esterified &alpha-tocopherol and tocotrienols in palm oils. J Jpn Oil Chem Soc 1981, 30(9):590-591.
7. Qureshi AA, Mo H, Packer L, Peterson DM: Isolation and identification of novel tocotrienols from rice bran with hypocholesterolemic, antioxidant, and antitumor properties. J Agric Food Chem 2000, 48(8):3130-3140.
8. Tan B, Brzuskiewicz L: Separation of tocopherol and tocotrienol isomers using normal-and reverse-phase liquid chromatography. Anal Biochem 1989, 180(2):368-373.
9. Aggarwal BB, Sundaram C, Prasad S, Kannappan R: Tocotrienols, the vitamin E of the 21st century: its potential against cancer and other chronic diseases. Biochem Pharmacol 2010, 80(11):1613-1631.
10. Sen CK, Khanna S, Roy S: Tocotrienols: vitamin E beyond tocopherols. Life Sci 2006, 78(18):2088-2098.
11. Pearce BC, Parker RA, DeasonME, Dischino DD, Gillespie E, Qureshi AA, Volk K, Wright JJ: Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols. J Med Chem1994, 37(4):526-541.
12. Pearce BC, Parker RA, Deason ME, Qureshi AA, Wright JJ: Hypocholesterolemic activity of synthetic and natural tocotrienols. J Med Chem 1992, 35(20):3595-3606.
13. Serbinova E, Kagan V, Han D, Packer L: Free radical recycling and intramembrane mobility in the antioxidant properties of alphatocopherol and alpha-tocotrienol. Free Radic Biol Med 1991, 10(5):263-275.
14. Serbinova EA, Packer L: Antioxidant properties of alpha-tocopherol and alpha-tocotrienol. Methods Enzymol 1994, 234:354-366.
15. Suzuki YJ, Tsuchiya M, Wassall SR, Choo YM, Govil G, Kagan VE, Packer L: Structural and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: implication to the molecular mechanism of their antioxidant potency. Biochemistry 1993, 32(40):10692-10699.
16. Hensley K, Benaksas EJ, Bolli R, Comp P, Grammas P, Hamdheydari L, Mou S, Pye QN, Stoddard MF, Wallis G, Williamson KS, West M, Wechter WJ, Floyd RA: New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine. Free Rad Biol Med 2004, 36(1):1-15.
17. Morris VC, Levander OA: Selenium content of foods. J Nutr 1970, 100:1383-1388.
18. Schrauzer GN: Nutritional selenium supplements: product types, quality, and safety. J Am Coll Nutr 2001, 20:1-4.
19. Harris PL, Quaife ML, Swanson WJ: Vitamin E content of foods. J Nutr 1950, 40:367-381.
20. Reagan-Shaw S, Nihal M, Ahsan H, Mukhtar H, Ahmad N: Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl-2 ratio. Prostate 2008, 68(15):1624-1634.
21. Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Mäenpää H, Teerenhovi L, Koss L, Virolainen M, Edwards BK: Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 1998, 90:440-446.
22. Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S, Estaquio C, Hercberg S: Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.-MAX trial. Int J Cancer 2005, 116:182-186.
23. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002, 360:23-33.
24. Rodriguez C, Jacobs EJ, Mondul AM, Calle EE, McCullough ML, Thun MJ: Vitamin E supplements and risk of prostate cancer in U.S. men. Cancer Epidemiol Biomarker Prev 2004, 13:378-382.
25. The HOPE and HOPE-TOO Trial Investigators: Effects of long term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005, 293:1338-1347.
26. Wright ME, Weinstein SJ, Lawson KA, Albanes D, Subar AF, Dixon LB, Mouw T, Schatzkin A, Leitzmann MF: Supplemental and dietary vitamin e intakes and risk of prostate cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev 2007, 16:1128-1135.
27. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD III, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz PA, Santella RM, Albanes D, Taylor PR, Probstfield JL, Jagpal TJ, Crowley JJ, et al: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009, 301:39-51.
28. Ledesma MC, Jung-Hynes B, Schmit TL, Kumar R, Mukhtar H, Ahmad N: Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 2011, 17(1-2):134-143.
29. Theriault A, Chao JT, Wang Q, Gapor A, Adeli K: Tocotrienol: a review of its therapeutic potential. Clin Biochem 1999, 32(5):309-319.
30. Jensen SK, Lauridsen C: Alpha-tocopherol stereoisomers. Vitam Horm 2007, 76:281-308.
31. Joffe M, Harris P: The biological potency of the natural tocopherols and certain derivatives. J Am Chem Soc 1943, 65:925-927.
32. Burton G, Ingold K: The antioxidant activity of vitamin E and relative chain-breaking phenolic antioxidants in vitro. J Am Chem Soc 1981, 103:6472-6477.
33. Hosomi A, Arita M, Sato Y, Kiyose C, Ueda T, Igarashi O, Arai H, Inoue K: Affinity for alpha-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett 1997, 409:105-108.
34. Lee E, Choi MK, Lee YJ, Ku JL, Kim KH, Choi JS, Lim SJ: Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alphatocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells. Carcinogenesis 2006, 27:2308-2315.
35. Bendich A, Machlin LJ: Safety of oral intake of vitamin E. Am J Clin Nutr 1988, 48:612-619.
36. Wechter WJ, Kantoci D, Murray ED Jr, D'Amico DC, Jung ME, Wang WH: A new endogenous natriuretic factor: LLU-a. Proc Natl Acad Sci U S A 1996, 93:6002-6007.
37. Freiser H, Jiang Q: Gamma-tocotrienol and gamma-tocopherol are primarily metabolized to conjugated 2-(beta-carboxyethyl)-6-hydroxy-2,7,8-tri methyl chroman and sulfated long-chain carboxy chromanols in rats. J Nutr 2009, 139:884-889.
38. Bardowell SA, Ding X, Parker RS: Disruption of P450-mediated vitamin E hydroxylase activities alters vitaminE status in tocopherol supplemented mice and reveals extra-hepatic vitamin E metabolism. J Lipid Res 2012, 53:2667-2676.
39. Bardowell SA, Duan F, Manor D: Disruption of mouse cytochrome p4504f14(Cyp4f14gene) causes severe perturbations in vitamin E metabolism. J Biol Chem 2012, 287:26077-26086.
40. Jiang Q, Jiang Z, Hall YJ, Jang Y, Snyder PW, Bain C, Huang J, Jannasch A, Cooper B, Wang Y, Ten Moreland MS, Ames BN: γ-Tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice. Free Radic Biol Med 2013, 65:1069-1077.
41. Jiang Q, Yin X, Lill MA, Danielson ML, Freiser H, Huang J: Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. Proc Natl Acad Sci U S A 2008, 105:20464-20469.
42. Jiang Z, Yin X, Jiang Q: Natural forms of vitamin E and 130-carboxychro manol, a long-chain vitamin E metabolite, inhibit leukotriene generation from stimulated neutrophils by blocking calcium in flux and suppressing 5-lipoxygenase activity, respectively. J Immunol 2011, 186:1173-1179.
43. Birringer M, Lington D, Vertuani S, Manfredini S, Scharlau D, Glei M, Ristow M: Proapoptotic effects of long-chain vitamin E metabolites in HepG2 cells are mediated by oxidative stress. Free Radic Biol Med 2010, 49:1315-1322.
44. Jiang Q: Natural forms of vitamin E: metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapy. Free Radic Biol Med 2014, 72C:76-90.
45. Galli F, Azzi A: Present trends in vitamin E research. Biofactors 2010, 36:33-42.
46. Ju J, Picinich SC, Yang Z, Zhao Y, Suh N, Kong AN, Yang CS: Cancerpreventive activities of tocopherols and tocotrienols. Carcinogenesis 2010, 31:533-542.
47. Constantinou C, Papas A, Constantinou AI: Vitamin E and cancer: an insight into the anticancer activities of vitamin E isomers and analogs. Int J Cancer 2008, 123:739-752.
48. Barve A, Khor TO, Nair S, Reuhl K, Suh N, Reddy B, Newmark H, Kong AN: Gamma-tocopherol-enriched mixed tocopherol diet inhibits prostate carcinogenesis in TRAMP mice. Int J Cancer 2009, 124:1693-1699.
49. Lu G, Xiao H, Li GX, Picinich SC, Chen YK, Liu A, Lee MJ, Loy S, Yang CS: A gamma-tocopherol-rich mixture of tocopherols inhibits chemically induced lung tumorigenesis in A/J mice and xenograft tumor growth. Carcinogenesis 2010, 31:687-694.
50. Yu W, Jia L, Park SK, Li J, Gopalan A, Simmons-Menchaca M, Sanders BG, Kline K: Anticancer actions of natural and synthetic vitamin E forms: RRR-alpha-tocopherol blocks the anticancer actions of gamma-tocopherol. Mol Nutr Food Res 2009, 53:1573-1581.
51. Jiang Q, Moreland M, Ames BN, Yin X: A combination of aspirin and gamma-tocopherol is superior to that of aspirin and alpha-tocopherol in anti-inflammatory action and attenuation of aspirin-induced adverse effects. J Nutr Biochem 2009, 20:894-900.
52. Cooney RV, Franke AA, Harwood PJ, Hatch-Pigott V, Custer LJ, Mordan LJ: Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alpha-tocopherol. Proc Natl Acad Sci U S A 1993, 90:1771-1775.
53. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN: Gamma-tocopherol traps mutagenic electrophiles such as NO (X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci U S A 1997, 94:3217-3222.
54. Jiang Q, Christen S, Shigenaga MK, Ames BN: Gamma-Tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001, 74:714-722.
55. Brigelius-Flohe R, Traber MG: Vitamin E: function and metabolism. FASEB J 1999, 13:1145-1155.
56. Moya-Camarena SY, Jiang Q: The role of vitamin E forms in cancer prevention and therapy-studies in human intervention trials and animal models. In Nutraceuticals and Cancer. Edited by Sarkar FH. New York: Springer; 2012:323-354.
57. Myung SK, Ju W, Cho B, Oh SW, Park SM, Koo BK, Park BJ, Korean Meta-Analysis Study Group: Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ 2013, 346:f10.
58. Atkinson J, Epand RF, Epand RM: Tocopherols and tocotrienols in membranes: a critical review. Free Radic Biol Med 2008, 44(5):739-764.
59. Qureshi AA, Bradlow BA, Brace L, Manganello J, Peterson DM, Pearce BC, Wright JJ, Gapor A, Elson CE: Response of hypercholesterolemic subjects to administration of tocotrienols. Lipids 1995, 30(12):1171-1177.
60. Agarwal MK, Agarwal ML, Athar M, Gupta S: Tocotrienol-rich fraction of palm oil activates p53, modulates Bax/Bcl2 ratio and induces apoptosis independent of cell cycle association. Cell Cycle 2004, 3(2):205-211.
61. Comitato R, Leoni G, Canali R, Ambra R, Nesaretnam K, Virgili F: Tocotrienols activity in MCF-7 breast cancer cells: involvement of ERbeta signal transduction. Mol Nutr Food Res 2010, 54(5):669-678.
62. Shun MC, Yu W, Gapor A, Parsons R, Atkinson J, Sanders BG, Kline K: Pro-apoptotic mechanisms of action of a novel vitamin E analog (alpha-TEA) and a naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human breast cancer cells. Nutr Cancer 2004, 48(1):95-105.
63. Pierpaoli E, Viola V, Barucca A, Orlando F, Galli F, Provinciali M: Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice. Carcinogenesis 2013, 34(6):1352-1360.
64. Samant GV, Wali VB, Sylvester PW: Anti-proliferative effects of gamma-tocotrienol on mammary tumour cells are associated with suppression of cell cycle progression. Cell Prolif 2010, 43(1):77-83.
65. Elangovan S, Hsieh TC, Wu JM: Growth inhibition of human MDA-mB-231 breast cancer cells by delta-tocotrienol is associated with loss of cyclin D1/CDK4 expression and accompanying changes in the state of phosphorylation of the retinoblastoma tumor suppressor gene product. Anticancer Res 2008, 28(5A):2641-2647.
66. Wali VB, Bachawal SV, Sylvester PW: Combined treatment of gamma-tocotrienol with statins induce mammary tumor cell cycle arrest in G1. Exp Biol Med (Maywood) 2009, 234(6):639-650.
67. Xu WL, Liu JR, Liu HK, Qi GY, Sun XR, Sun WG, Chen BQ: Inhibition of proliferation and induction of apoptosis by gamma-tocotrienol in human colon carcinoma HT-29 cells. Nutrition 2009, 25(5):555-566.
68. Sakai M, Okabe M, Tachibana H, Yamada K: Apoptosis induction by gamma-tocotrienol in human hepatoma Hep3B cells. J Nutr Biochem 2006, 17(10):672-676.
69. Sun W, Wang Q, Chen B, Liu J, Liu H, Xu W: Gamma-tocotrienol-induced apoptosis in human gastric cancer SGC-7901 cells is associated with a suppression in mitogen-activated protein kinase signalling. Br J Nutr 2008, 99(6):1247-1254.
70. Wada S, Satomi Y, Murakoshi M, Noguchi N, Yoshikawa T, Nishino H: Tumor suppressive effects of tocotrienol in vivo and in vitro. Cancer Lett 2005, 229(2):181-191.
71. Kashiwagi K, Harada K, Yano Y, Kumadaki I, Hagiwara K, Takebayashi J, Kido W, Virgona N, Yano T: A redox-silent analogue of tocotrienol inhibits hypoxic adaptation of lung cancer cells. Biochem Biophys Res Commun 2008, 365(4):875-881.
72. Nakashima K, Virgona N, Miyazawa M, Watanabe T, Yano T: The tocotrienolrich fraction from rice bran enhances cisplatin-induced cytotoxicity in human mesothelioma H28 cells. Phytother Res 2010, 24(9):1317-1321.
73. Chang PN, Yap WN, Lee DT, Ling MT, Wong YC, Yap YL: Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells. Nutr Cancer 2009, 61(3):357-366.
74. McAnally JA, Gupta J, Sodhani S, Bravo L, Mo H: Tocotrienols potentiate lovastatin-mediated growth suppression in vitro and in vivo. Exp Biol Med (Maywood) 2007, 232(4):523-531.
75. Hussein D, Mo H: d-delta-Tocotrienol-mediated suppression of the proliferation of human PANC-1, MIA PaCa-2, and BxPC-3 pancreatic carcinoma cells. Pancreas 2009, 38(4):e124-e136.
76. Constantinou C, Hyatt JA, Vraka PS, Papas A, Papas KA, Neophytou C, Hadjivassiliou V, Constantinou AI: Induction of caspase-independent programmed cell death by vitamin E natural homologs and synthetic derivatives. Nutr Cancer 2009, 61(6):864-874.
77. Nesaretnam K, Stephen R, Dils R, Darbre P: Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status. Lipids 1998, 33(5):461-469.
78. Wada S: Chemoprevention of tocotrienols: the mechanism of antiproliferative effects. Forum Nutr 2009, 61:204-216.
79. Wali VB, Bachawal SV, Sylvester PW: Endoplasmic reticulum stress mediates gamma-tocotrienol-induced apoptosis in mammary tumor cells. Apoptosis 2009, 14(11):1366-1377.
80. Comitato R, Nesaretnam K, Leoni G, Ambra R, Canali R, Bolli A, Marino M, Virgili F: A novel mechanism of natural vitamin E tocotrienol activity: involvement of ERbeta signal transduction. Am J Physiol Endocrinol Metab 2009, 297(2):E427-E437.
81. Nakagawa K, Shibata A, Yamashita S, Tsuzuki T, Kariya J, Oikawa S, Miyazawa T: In vivo angiogenesis is suppressed by unsaturated vitamin E, tocotrienol. J Nutr 2007, 137(8):1938-1943.
82. Weng-Yew W, Selvaduray KR, Ming CH, Nesaretnam K: Suppression of tumor growth by palm tocotrienols via the attenuation of angiogenesis. Nutr Cancer 2009, 61(3):367-373.
83. Har CH, Keong CK: Effects of tocotrienols on cell viability and apoptosis in normal murine liver cells (BNL CL.2) and liver cancer cells (BNL 1ME A.7R.1), in vitro. Asia Pac J Clin Nutr 2005, 14(4):374-380.
84. Wali VB, Bachawal SV, Sylvester PW: Suppression in mevalonate synthesis mediates antitumor effects of combined statin and gamma-tocotrienol treatment. Lipids 2009, 44(10):925-934.
85. Bachawal SV, Wali VB, Sylvester PW: Combined gamma-tocotrienol and erlotinib/gefitinib treatment suppresses Stat and Akt signaling in murine mammary tumor cells. Anticancer Res 2010, 30(2):429-437.
86. Rashid SA, Halim AS, Muhammad NA, Suppl A: The effect of vitamin E on basic fibroblast growth factor level in human fibroblast cell culture. Med J Malaysia 2008, 63:69-70.
87. Pierpaoli E, Viola V, Pilolli F, Piroddi M, Galli F, Provinciali M: Gamma-and delta-tocotrienols exert a more potent anticancer effect than alphatocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression. Life Sci 2010, 86(17-18):668-675.
88. Wu SJ, Ng LT: Tocotrienols inhibited growth and induced apoptosis in human HeLa cells through the cell cycle signaling pathway. Integr Cancer Ther 2010, 9(1):66-72.
89. Eitsuka T, Nakagawa K, Miyazawa T: Down-regulation of telomerase activity in DLD-1 human colorectal adenocarcinoma cells by tocotrienol. Biochem Biophys Res Commun 2006, 348(1):170-175.
90. Stolzenberg-Solomon RZ, Sheffler-Collins S, Weinstein S, Garabrant DH, Mannisto S, Taylor P, Virtamo J, Albanes D: Vitamin E intake, alphatocopherol status, and pancreatic cancer in a cohort of male smokers. Am J Clin Nutr 2009, 89(2):584-591.
91. Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB: Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaBregulated gene products. Cancer Res 2007, 67:3853-3861.
92. Mahon PC, Baril P, Bhakta V, Chelala C, Caulee K, Harada T, Lemoine NR: S100A4 contributes to the suppression of BNIP3 expression, chemoresistance, and inhibition of apoptosis in pancreatic cancer. Cancer Res 2007, 67:6786-6795.
93. Kürbitz C, Heise D, Redmer T, Goumas F, Arlt A, Lemke J, Rimbach G, Kalthoff H, Trauzold A: Epicatechin gallate and catechin gallate are superior to epigallocatechin gallate in growth suppression and anti-inflammatory activities in pancreatic tumor cells. Cancer Sci 2011, 102:728-734.
94. Murtaza I, Adhami VM, Hafeez BB, Saleem M, Mukhtar H: Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB. Int J Cancer 2009, 125:2465-2473.
95. Miyazawa T, Shibata A, Sookwong P, Kawakami Y, Eitsuka T, Asai A, Oikawa S, Nakagawa K: Antiangiogenic and anticancer potential of unsaturated vitamin E (tocotrienol). J Nutr Biochem 2009, 20:79-86.
96. Ling MT, Luk SU, Al-Ejeh F, Khanna KK: Tocotrienol as a potential anticancer agent. Carcinogenesis 2012, 33(2):233-239.
97. Husain K, Francois RA, Hutchinson SZ, Neuger AM, Lush R, Coppola D, Sebti S, Malafa MP: Vitamin E delta-tocotrienol levels in tumor and pancreatic tissue of mice after oral administration. Pharmacology 2009, 83:157-163.
98. Husain K, Francois RA, Yamauchi T, Perez M, Sebti SM, Malafa MP: Vitamin E d-tocotrienol augments the antitumor activity of gemcitabine and suppresses constitutive NF-κB activation in pancreatic cancer. Mol Cancer Ther 2011, 10(12):2363-2372.
99. Nesaretnam K, Meganathan P, Veerasenan SD, Selvaduray KR: Tocotrienols and breast cancer: the evidence to date. Genes Nutr 2012, 7(1):3-9.
100. Nesaretnam K, Selvaduray KR, Abdul Razak G, Veerasenan SD, Gomez PA: Effectiveness of tocotrienol-rich fraction combined with tamoxifen in the management of women with early breast cancer: a pilot clinical trial. Breast Cancer Res 2010, 12(5):R81.
101. Ahn KS, Sethi G, Krishnan K, Aggarwal BB: 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 2007, 282(1):809-820.
102. Shirode AB, Sylvester PW: Synergistic anticancer effects of combined γ-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFκB signaling. Biomed Pharmacother 2010, 64(5):327-332.
103. Kuhad A, Chopra K: Attenuation of diabetic nephropathy by tocotrienol: involvement of NFkB signaling pathway. Life Sci 2009, 84(9-10):296-301.
104. Norazlina M, Lee PL, Lukman HI, Nazrun AS, Ima-Nirwana S: Effects of vitamin E supplementation on bone metabolism in nicotine-treated rats. Singapore Med J 2007, 48(3):195-199.
105. Ahmad NS, Khalid BA, Luke DA, Ima Nirwana S: Tocotrienol offers better protection than tocopherol from free radical-induced damage of rat bone. Clin Exp Pharmacol Physiol 2005, 32(9):761-770.
106. Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Tomita S, Shirakawa H, Komai M, Miyazawa T: Tocotrienol inhibits secretion of angiogenic factors from human colorectal adenocarcinoma cells by suppressing hypoxia-inducible factor-1alpha. J Nutr 2008, 138(11):2136-2142.
107. Wu SJ, Liu PL, Ng LT: 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 2008, 52(8):921-929.
108. Lee SP, Mar GY, Ng LT: Effects of tocotrienol-rich fraction on exercise endurance capacity and oxidative stress in forced swimming rats. Eur J Appl Physiol 2009, 107(5):587-595.
109. Newaz MA, Nawal NN: Effect of gamma-tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp Hypertens 1999, 21(8):1297-1313.
110. Hsieh TC, Wu JM: Suppression of cell proliferation and gene expression by combinatorial synergy of EGCG, resveratrol and gamma-tocotrienol in estrogen receptor-positive MCF-7 breast cancer cells. Int J Oncol 2008, 33(4):851-859.
111. Adam A, Marzuki A, Ngah WZ, Top GM: Nitrofurantoin-induced hepatic and pulmonary biochemical changes in mice fed different vitamin E doses. Pharmacol Toxicol 1996, 79(6):334-339.
112. Renuka Devi R, Arumughan C: Antiradical efficacy of phytochemical extracts from defatted rice bran. Food Chem Toxicol 2007, 45(10):2014-2021.
113. Ngah WZ, Jarien Z, San MM, Marzuki A, Top GM, Shamaan NA, Kadir KA: Effect of tocotrienols on hepatocarcinogenesis induced by 2-acetylaminofluorene in rats. Am J Clin Nutr 1991, 53(4 Suppl):1076S-1081S.
114. Shamaan NA, Wan Ngah WZ, Ibrahim R, Jarien Z, Top AG, Abdul Kadir K: Effect of tocotrienol on the activities of cytosolic glutathione-dependent enzymes in rats treated with 2-acetylaminofluorene. Biochem Pharmacol 1993, 45(7):1517-1519.
115. Makpol S, Shamaan NA, Jarien Z, Top AG, Khalid BA, Wan Ngah WZ: Different starting times of alpha-tocopherol and gamma-tocotrienol supplementation and tumor marker enzyme activities in the rat chemically induced with cancer. Gen Pharmacol 1997, 28(4):589-592.
116. Ong FB, Wan Ngah WZ, Shamaan NA, Md Top AG, Marzuki A, Khalid AK: Glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured rat hepatocytes treated with tocotrienol and tocopherol. Comp Biochem Physiol Part C Pharmacol Toxicol Endocrinol 1993, 106(1):237-240.
117. Palozza P, Verdecchia S, Avanzi L, Vertuani S, Serini S, Iannone A, Manfredini S: Comparative antioxidant activity of tocotrienols and the novel chromanyl-polyisoprenyl molecule FeAox-6 in isolated membranes and intact cells. Mol Cell Biochem 2006, 287(1-2):21-32.
118. Osakada F, Hashino A, Kume T, Katsuki H, Kaneko S, Akaike A: Alpha-tocotrienol provides the most potent neuroprotection among vitamin E analogs on cultured striatal neurons. Neuropharmacology 2004, 47(6):904-915.
119. Nakano M, Onodera A, Saito E, Tanabe M, Yajima K, Takahashi J, Nguyen VC: Effect of astaxanthin in combination with alpha-tocopherol or ascorbic acid against oxidative damage in diabetic ODS rats. J Nutr Sci Vitaminol (Tokyo) 2008, 54(4):329-334.
120. Wan Nazaimoon WM, Khalid BA: Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycemic control in streptozotocin-induced diabetic rats. Malays J Pathol 2002, 24(2):77-82.
121. Budin SB, Othman F, Louis SR, Bakar MA, Das S, Mohamed J: The effects of palm oil tocotrienol-rich fraction supplementation on biochemical parameters, oxidative stress and the vascular wall of streptozotocin-induced diabetic rats. Clinics (Sao Paulo) 2009, 64(3):235-244.
122. Kuhad A, Bishnoi M, Tiwari V, Chopra K: Suppression of NF-kappabeta signaling pathway by tocotrienol can prevent diabetes associated cognitive deficits. Pharmacol Biochem Behav 2009, 92(2):251-259.
123. Kuhad A, Chopra K: Tocotrienol attenuates oxidative-nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy. Neuropharmacology 2009, 57(4):456-462.
124. Tiwari V, Kuhad A, Bishnoi M, Chopra K: Chronic treatment with tocotrienol, an isoform of vitamin E, prevents intracerebroventricular streptozotocin-induced cognitive impairment and oxidative-nitrosative stress in rats. Pharmacol Biochem Behav 2009, 93(2):183-189.
125. Tiwari V, Kuhad A, Chopra K: Neuroprotective effect of vitamin E isoforms against chronic alcohol-induced peripheral neurotoxicity: possible involvement of oxidative-nitrodative stress. Phytother Res 2012, 26(11):1738-1745.
126. Siddiqui S, Rashid Khan M, Siddiqui WA: Comparative hypoglycemic and nephroprotective effects of tocotrienol rich fraction (TRF) from palm oil and rice bran oil against hyperglycemia induced nephropathy in type 1 diabetic rats. Chem Biol Interact 2010, 188(3):651-658.
127. Siddiqui S, Ahsan H, Khan MR, Siddiqui WA: Protective effects of tocotrienols against lipid-induced nephropathy in experimental type-2 diabetic rats by modulation in TGF-beta expression. Toxicol Appl Pharmacol 2013, 273(2):314-324.
128. Kanaya Y, Doi T, Sasaki H, Fujita A, Matsuno S, Okamoto K, Nakano Y, Tsujiwaki S, Furuta H, Nishi M, Tsuno T, Taniguchi H, Nanjo K: Rice bran extract prevents the elevation of plasma peroxylipid in KKAy diabetic mice. Diabetes Res Clin Pract 2004, 66(Suppl 1):S157-S160.
129. Yoshida Y, Hayakawa M, Habuchi Y, Itoh N, Niki E: Evaluation of lipophilic antioxidant efficacy in vivo by the biomarkers hydroxyoctadecadienoic acid and isoprostane. Lipids 2007, 42(5):463-472.
130. Fang F, Kang Z, Wong C: Vitamin E tocotrienols improve insulin sensitivity through activating peroxisome proliferator-activated receptors. Mol Nutr Food Res 2010, 54(3):345-352.
131. Qureshi AA, Qureshi N, Hasler-Rapacz JO, Weber FE, Chaudhary V, Crenshaw TD, Gapor A, Ong AS, Chong YH, Peterson D: Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited hyperlipidemias. Am J Clin Nutr 1991, 53(4 Suppl):1042S-1046S.
132. Qureshi AA, Qureshi N, Wright JJ, Shen Z, Kramer G, Gapor A, Chong YH, DeWitt G, Ong A, Peterson DM: Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee). Am J Clin Nutr 1991, 53(4 Suppl):1021S-1026S.
133. Hood RL, Sidhu GS: Effects of guar gum and tocotrienols on cholesterol metabolism on the Japanese quail. Nutr Res 1992, 12:117S-127S.
134. Parker RA, Pearce BC, Clark RW, Gordon DA, Wright JJ: Tocotrienols regulate cholesterol production in mammalian cells by posttranscriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 1993, 268(15):11230-11238.
135. Qureshi N, Qureshi AA: Novel hypercholesterolemic agents with antioxidant properties. In Vitamin E in Health and Disease. Edited by Packer L, Fuchs J. New York: Marcel Dekker; 1993:247-267.
136. Minhajuddin M, Beg ZH, Iqbal J: Hypolipidemic and antioxidant properties of tocotrienol rich fraction isolated from rice bran oil in experimentally induced hyperlipidemic rats. Food Chem Toxicol 2005, 43(5):747-753.
137. Watkins T, Lenz P, Gapor A, Struck M, Tomeo A, Bierenbaum M: Gamma-Tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed atherogenic diets. Lipids 1993, 28(12):1113-1118.
138. Khor HT, Chieng DY, Ong KK: Tocotrienols inhibit HMG-CoA reductase activity in the guinea pig. Nutr Res 1995, 15:537-544.
139. Iqbal J, Minhajuddin M, Beg ZH: Suppression of 7,12-dimethylbenz[alpha] anthracene-induced carcinogenesis and hypercholesterolaemia in rats by tocotrienol-rich fraction isolated from rice bran oil. Eur J Cancer Prev 2003, 12(6):447-453.
140. Magosso E, Ansari MA, Gopalan Y, Shuaib IL, Wong JW, Khan NA, Abu Bakar MR, Ng BH, Yuen KH: Tocotrienols for normalisation of hepatic echogenic response in nonalcoholic fatty liver: a randomised placebo-controlled clinical trial. Nutr J 2013, 12(1):166.
141. Burdeos GC, Nakagawa K, Watanabe A, Kimura F, Miyazawa T: Gamma-tocotrienol attenuates triglyceride through effect on lipogenic gene expression in mouse hepatocellular carcinoma Hepa 1-6. J Nutr Sci Vitaminol 2013, 59:148-151.
142. Muto C, Yachi R, Aoki Y, Koike T, Igarashi O, Kiyose C: Gamma-tocotrienol reduces the triacylglycerol level in rat primary hepatocytes through regulation of fatty acid metabolism. J Clin Biochem Nutr 2013, 52(1):32-37.
143. Kooyenga DK, Geller M, Watkins TR, Gapor A, Diakoumakis E, Bierenbaum ML: Palm oil antioxidant effects in patients with hyperlipidaemia and carotid stenosis-2 year experience. Asia Pac J Clin Nutr 1997, 6(1):72-75.
144. Tan B, Mueller AM: Tocotrienols in cardiometabolic diseases. In Tocotrienols: Vitamin E beyond Tocopherol. Edited by Watson RR, Preedy VR. AOCS/CRC Press, Taylor and Francis Group; 2008:257-273.
145. Mahalingam D, Radhakrishnan AK, Amom Z, Ibrahim N, Nesaretnam K: Effects of supplementation with tocotrienol-rich fraction on immune response to tetanus toxoid immunization in normal healthy volunteers. Eur J Clin Nutr 2011, 65(1):63-69.
146. Ren Z, Pae M, Dao MC, Smith D, Meydani SN, Wu D: Dietary supplementation with tocotrienols enhances immune function in C57BL/ 6 mice. J Nutr 2010, 140(7):1335-1341.
147. Gu JY, Wakizono Y, Sunada Y, Hung P, Nonaka M, Sugano M, Yamada K: Dietary effect of tocopherols and tocotrienols on the immune function of spleen and mesenteric lymph node lymphocytes in brown Norway rats. Biosci Biotechnol Biochem 1999, 63(10):1697-1702.
148. Radhakrishnan AK, Mahalingam D, Selvaduray KR, Nesaretnam K: Supplementation with natural forms of vitamin e augments antigen-specific Th1-type immune response to tetanus toxoid. Biomed Res Int 2013, 2013:782067.
149. Vasanthi HR, Parameswari RP, Das DK: Multifaceted role of tocotrienols in cardioprotection supports their structure: function relation. Genes Nutr 2012, 7(1):19-28.
150. Chao JT, Gapor A, Theriault A: Inhibitory effect of delta-tocotrienol, a HMG CoA reductase inhibitor, on monocyte-endothelial cell adhesion. J Nutr Sci Vitaminol (Tokyo) 2002, 48(5):332-337.
151. Theriault A, Chao JT, Gapor A: Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes. Atherosclerosis 2002, 160(1):21-30.
152. Koba K, Abe K, Ikeda I, Sugano M: Effects of alpha-tocopherol and tocotrienols on blood pressure and linoleic acid metabolism in the spontaneously hypertensive rat (SHR). Biosci Biotechnol Biochem 1992, 56(9):1420-1423.
153. Chou TW, Ma CY, Cheng HH, Chen YY, Lai MH: A rice bran oil diet improves lipid abnormalities and suppress hyperinsulinemic responses in rats with streptozotocin/nicotinamide-induced type 2 diabetes. J Clin Biochem Nutr 2009, 45(1):29-36.
154. Nafeeza MI, Norzana AG, Jalaluddin HL, Gapor MT: The effects of a tocotrienol-rich fraction on experimentally induced atherosclerosis in the aorta of rabbits. Malays J Pathol 2001, 23(1):17-25.
155. Das S, Powell SR, Wang P, Divald A, Nesaretnam K, Tosaki A, Cordis GA, Maulik N, Das DK: Cardioprotection with palm tocotrienol: antioxidant activity of tocotrienol is linked with its ability to stabilize proteasomes. Am J Physiol Heart Circ Physiol 2005, 289(1):H361-H367.
156. Retraction in: Am J Physiol Heart Circ Physiol 2012, 302(11):H2447.
157. Qureshi AA, Peterson DM, Hasler-Rapacz JO, Rapacz J: Novel tocotrienols of rice bran suppress cholesterogenesis in hereditary hypercholesterolemic swine. J Nutr 2001, 131(2):223-230.
158. Esterhuyse AJ, du Toit EF, Benadè AJ, Van Rooyen J: Dietary red palm oil improves reperfusion cardiac function in the isolated perfused rat heart of animals fed a high cholesterol diet. Prostaglandins Leukot Essent Fatty Acids 2005, 72(3):153-161.
159. Das M, Das S, Wang P, Powell SR, Das DK: Caveolin and proteasome in tocotrienol mediated myocardial protection. Cell Physiol Biochem 2008, 22(1-4):287-294.
160. Sen CK, Khanna S, Roy S, Packer L: Molecular basis of vitamin E action: tocotrienol potently inhibits glutamate-induced pp 60(c-Src) kinase activation and death of HT4 neuronal cells. J Biol Chem 2000, 275(17):13049-13055.
161. Sen CK, Khanna S, Roy S: Tocotrienol: the natural vitamin E to defend the nervous system? Ann N Y Acad Sci 2004, 1031:127-142.
162. Khanna S, Roy S, Slivka A, Craft TK, Chaki S, Rink C, Notestine MA, DeVries AC, Parinandi NL, Sen CK: Neuroprotective properties of the natural vitamin E alpha-tocotrienol. Stroke 2005, 36(10):2258-2264.
163. Khanna S, Roy S, Parinandi NL, Maurer M, Sen CK: Characterization of the potent neuroprotective properties of the natural vitamin E alpha-tocotrienol. J Neurochem 2006, 98(5):1474-1486.
164. Khanna S, Parinandi NL, Kotha SR, Roy S, Rink C, Bibus D, Sen CK: Nanomolar vitamin E alpha-tocotrienol inhibits glutamate-induced activation of phospholipase A2 and causes neuroprotection. J Neurochem 2010, 112(5):1249-1260.
165. Khanna S, Roy S, Park HA, Sen CK: Regulation of c-Src activity in glutamate-induced neurodegeneration. J Biol Chem 2007, 282(32):23482-23490.
166. Liu X, Yamada N, Osawa T: Assessing the neuroprotective effect of antioxidant food factors by application of lipid-derived dopamine modification adducts. Methods Mol Biol 2010, 594:263-273.
167. Fukui K, Ushiki K, Takatsu H, Koike T, Urano S: Tocotrienols prevent hydrogen peroxide-induced axon and dendrite degeneration in cerebellar granule cells. Free Radic Res 2012, 46(2):184-193.
168. Liu X, Yamada N, Osawa T: Assessing the neuroprotective effect of antioxidative food factors by application of lipid-derived dopamine modification adducts. Methods Mol Biol 2009, 580:143-152.
169. Sen CK, Rink C, Khanna S: Palm oil-derived natural vitamin E alpha-tocotrienol in brain health and disease. J Am Coll Nutr 2010, 29(3 Suppl):314S-323S.
170. Sen CK, Khanna S, Rink C, Roy S: Tocotrienols: the emerging face of natural vitamin E. Vitam Horm 2007, 76:203-261.
171. Park HA, Kubicki N, Gnyawali S, Chan YC, Roy S, Khanna S, Sen CK: Natural vitamin E a-tocotrienol protects against ischemic stroke by induction of multidrug resistance-associated protein 1. Stroke 2011, 42(8):2308-2314.
172. Tiwari V, Kuhad A, Chopra K: Tocotrienol ameliorates behavioral and biochemical alterations in the rat model of alcoholic neuropathy. Pain 2009, 145(1-2):129-135.
173. Tiwari V, Kuhad A, Chopra K: Suppression of neuro-inflammatory signaling cascade by tocotrienol can prevent chronic alcohol-induced cognitive dysfunction in rats. Behav Brain Res 2009, 203(2):296-303.
174. Hermizi H, Faizah O, Ima-Nirwana S, Ahmad Nazrun S, Norazlina M: Beneficial effects of tocotrienol and tocopherol on bone histomorphometric parameters in Sprague-Dawley male rats after nicotine cessation. Calcif Tissue Int 2009, 84(1):65-74.
175. Norazlina M, Hermizi H, Faizah O, Nazrun AS, Norliza M, Ima-Nirwana S: Vitamin E reversed nicotine-induced toxic effects on bone biochemical markers in male rats. Arch Med Sci 2010, 6(4):505-512.
176. Mehat MZ, Shuid AN, Mohamed N, Muhammad N, Soelaiman IN: Beneficial effects of vitamin E isomer supplementation on static and dynamic bone histomorphometry parameters in normal male rats. J Bone Miner Metab 2010, 28(5):503-509.
177. Shuid AN, Mehat Z, Mohamed N, Muhammad N, Soelaiman IN: Vitamin E exhibits bone anabolic actions in normal male rats. J Bone Miner Metab 2010, 28(2):149-156.
178. Maniam S, Mohamed N, Shuid AN, Soelaiman IN: Palm tocotrienol exerted better antioxidant activities in bone than alpha-tocopherol. Basic Clin Pharmacol Toxicol 2008, 103(1):55-60.
179. Norazlina M, Ima-Nirwana S, Abul Gapor MT, Abdul Kadir Khalid B: Tocotrienols are needed for normal bone calcification in growing female rats. Asia Pac J Clin Nutr 2002, 11(3):194-199.
180. Ima-Nirwana S, Kiftiah A, Sariza T, Gapor MT, Khalid BA: Palm vitamin E improves bone metabolism and survival rate in thyrotoxic rats. Gen Pharmacol 1999, 32(5):621-626.
181. Ima-Nirwana S, Suhaniza S: Effects of tocopherols and tocotrienols on body composition and bone calcium content in adrenalectomized rats replaced with dexamethasone. J Med Food 2004, 7(1):45-51.
182. Abdul-Majeed S, Mohamed N, Soelaiman IN: Effects of tocotrienol and lovastatin combination on osteoblast and osteoclast activity in estrogen-deficient osteoporosis. Evid Based Complement Alternat Med 2012, 2012:960742.
183. Soelaiman IN, Ming W, Abu Bakar R, Hashnan NA, Mohd Ali H, Mohamed N, Muhammad N, Shuid AN: Palm tocotrienol supplementation enhanced bone formation in oestrogen-deficient rats. Int J Endocrinol 2012, 2012:532862.
184. Azlina MF, Nafeeza MI, Khalid BA: A comparison between tocopherol and tocotrienol effects on gastric parameters in rats exposed to stress. Asia Pac J Clin Nutr 2005, 14(4):358-365.
185. Nafeeza MI, Kang TT: Synergistic effects of tocopherol, tocotrienol, and ubiquinone in indomethacin-induced experimental gastric lesions. Int J Vitam Nutr Res 2005, 75(2):149-155.
186. Ong FB, Wan Ngah WZ, Top AG, Khalid BA, Shamaan NA: Vitamin E, glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured hepatocytes of rats treated with carcinogens. Int J Biochem 1994, 26(3):397-402.
187. Brigelius-Flohe R: Induction of drug metabolizing enzymes by vitamin E. J Plant Physiol 2005, 162(7):797-802.
188. Zhou C, Tabb MM, Sadatrafiei A, Grün F, Blumberg B: Tocotrienols activate the steroid and xenobiotic receptor, SXR, and selectively regulate expression of its target genes. Drug Metab Dispos 2004, 32(10):1075-1082.
189. Bhatti GK, Bhatti JS, Kiran R, Sandhir R: Alterations in Ca2+ homeostasis and oxidative damage induced by ethion in erythrocytes of Wistar rats: ameliorative effect of vitamin E. Environ Toxicol Pharmacol 2011, 31(3):378-386.
190. Bhatti GK, Bhatti JS, Kiran R, Sandhir R: Biochemical and morphological perturbations in rat erythrocytes exposed to ethion: protective effect of vitamin E. Cell Mol Biol (Noisy-le-Grand) 2011, 57(1):70-79.
191. Patel V, Rink C, Gordillo GM, Khanna S, Gnyawali U, Roy S, Shneker B, Ganesh K, Phillips G, More JL, Sarkar A, Kirkpatrick R, Elkhammas EA, Klatte E, Miller M, Firstenberg MS, Chiocca EA, Nesaretnam K, Sen CK: Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients. J Nutr 2012, 142(3):513-519.
192. Yoshida M, Kimura H, Kyuki K, Ito M: Effect of combined vitamin E and insulin administration on renal damage in diabetic rats fed a high cholesterol diet. Biol Pharm Bull 2005, 28(11):2080-2086.
193. Gupta A, Chopra K: Effect of tocotrienols on iron-induced renal dysfunction and oxidative stress in rats. Drug Chem Toxicol 2009, 32(4):319-325.
194. Khan MR, Siddiqui S, Parveen K, Javed S, Diwakar S, Siddiqui WA: Nephroprotective action of tocotrienol-rich fraction (TRF) from palm oil against potassium dichromate (K2Cr2O7)-induced acute renal injury in rats. Chem Biol Interact 2010, 186(2):228-238.
195. Budin SB, Han KJ, Jayusman PA, Taib IS, Ghazali AR, Mohamed J: Antioxidant activity of tocotrienol rich fraction prevents fenitrothion-induced renal damage in rats. J Toxic Pathol 2013, 26(2):111-118.
196. Nowak G, Bakajsova D, Hayes C, Hauer-Jensen M, Compadre CM: Gamma-Tocotrienol protects against mitochondrial dysfunction and renal cell death. J Pharmacol Exp Ther 2012, 340(2):330-338.
197. Arrand JE, Michael BD: Recent advances in the study of ionizing radiation damage and repair. Int J Rad Biol 1992, 61(6):717-720.
198. Multhoff G, Radons J: Radiation, inflammation, and immune responses in cancer. Front Oncol 2012, 2:58.
199. Roos WP, Kaina B: DNA damage-induced cell death by apoptosis. Trend Mol Med 2006, 12(9):440-450.
200. Cheung BMY, Li C: Diabetes and hypertension: is there a common metabolic pathway? Curr Atherosclerosis Rep 2012, 14(2):160-166.
201. Dumont F, Roux AL, Bischoff P: Radiation countermeasure agents: an update. Exp Opinion Therp Patent 2010, 1:73-101.
202. Kulkarni S, Ghosh SP, Hauer-Jensen M, Kumar KS: Hematological targets of radiation damage. Curr Drug Target 2010, 11(11):1375-1385.
203. Farese AM, Herodin F, McKearn JP, Baum C, Burton E, MacVittie TJ: Acceleration of hematopoietic reconstitution with a synthetic cytokine (SC-55494) after radiation-induced bone marrow aplasia. Blood 1996, 87(2):581-591.
204. Ghosh SP, Kulkarni S, Hieber K, Toles R, Romanyukha L, Kao TC, Hauer-Jensen M, Kumar KS: Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector. Int J Rad Biol 2009, 85(7):598-606.
205. Kulkarni S, Ghosh SP, Satyamitra M, Mog S, Hieber K, Romanyukha L, Gambles K, Toles R, Kao TC, Hauer-Jensen M, Kumar KS: Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after total-body irradiation. Rad Res 2010, 173(6):738-747.
206. Berbée M, Fu Q, Boerma M, Wang J, Kumar KS, Hauer-Jensen M: γ-Tocotrienol ameliorates intestinal radiation injury and reduces vascular oxidative stress after total-body irradiation by an HMG-CoA Reductase-dependent mechanism. Rad Res 2009, 171(5):596-605.
207. Kulkarni SS, Cary LH, Gambles K, Hauer-Jensen M, Kumar KS, Ghosh SP: Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony stimulating factor. Int Immunopharmacol 2012, 14(4):495-503.
208. Laufs U, La Fata V, Plutzky J, Liao JK: Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998, 97:1129-1135.
209. Takemoto M, Liao JK: Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arterioscler Thromb Vasc Biol 2001, 21:1712-1719.
210. Kulkarni S, Chakraborty K, Kumar KS, Kao TC, Hauer-Jensen M, Ghosh SP: Synergistic radioprotection by gamma-tocotrienol and pentoxifylline: role of cAMP signaling. ISRN Radiol 2013. epub ehead of print.
211. Kim NY, Pae HO, Kim YC, Choi CK, Rim JS, Lee HS, Kim YM, Chung HT: Pentoxifylline potentiates nitric oxide production in interleukin-1betastimulated vascular smooth muscle cells through cyclic AMP-dependent protein kinase A pathway. Gen Pharmacol 2000, 35:205-211.
212. Zhang XP, Tada H, Wang Z, Hintze TH: cAMP signal transduction, a potential compensatory pathway for coronary endothelial NO production after heart failure. Arterioscler Thromb Vasc Biol 2002, 22:1273-1278.
213. Zhang XP, Hintze TH: cAMP signal transduction induces eNOS activation by promoting PKB phosphorylation. Am J Physiol Heart Circ Physiol 2006, 290:H2376-H2384.
214. Ernst E: Pentoxifylline for intermittent claudication: a critical review. Angiology 1994, 45(5):339-345.
215. Dettelbach HR, Aviado DM: Clinical pharmacology of pentoxifylline with special reference to its hemorrheologic effect for the treatment of intermittent claudication. J Clin Pharmacol 1985, 25(1):8-26.
216. Haddad P, Kalaghchi B, Amouzegar-Hashemi F: Pentoxifylline and vitamin E combination for superficial radiation induced fibrosis: a phase II clinical trial. Radiother Oncol 2005, 77(3):324-326.
217. Amano M, Monzen H, Suzuki M, Terai K, Andoh S, Tsumuraya A, Hasegawa T: Increase in tumor oxygenation and potentiation of radiation effects using pentoxifylline, vinpocetine and ticlopidine hydrochloride. J Rad Res 2005, 46(4):373-378.
218. Dion MW, Hussey DH, Osborne JW: The effect of pentoxifylline on early and late radiation injury following fractionated irradiation in C3H mice. Int J Rad Oncol Biol Phy 1989, 17(1):101-107.
219. Rübe CE, Wilfert F, Uthe D, Schmid KW, Knoop R, Willich N, Schuck A, Rübe C: Modulation of radiation induced tumour necrosis factor a (TNF-a) expression in the lung tissue by pentoxifylline. Radiother Oncol 2002, 64(2):177-187.
220. Berbée M, Fu Q, Garg S, Kulkarni S, Kumar KS, Hauer-Jensen M: Pentoxifylline enhances the radioprotective properties of γ-Tocotrienol: differential effects on the hematopoietic, gastrointestinal and vascular systems. Rad Res 2011, 175(3):297-306.
221. Nakamura H, Furukawa F, Nishikawa A, Miyauchi M, Son HY, Imazawa T, Hirose M: Oral toxicity of a tocotrienol preparation in rats. Food Chem Toxicol 2001, 39(8):799-805.
222. Fu JY, Che HL, Tan DM, Teng KT: Bioavailability of tocotrienols: evidence in human studies. Nutr Metab 2014, 11:p5.
223. Campbell SE, Rudder B, Phillips RB, Whaley SG, Stimmel JB, Leesnitzer LM, Lightner J, Dessus-Babus S, Duffourc M, Stone WL, Menter DG, Newman RA, Yang P, Aggarwal BB, Krishnan K: Gamma-Tocotrienol induces growth arrest through a novel pathway with TGFbeta2 in prostate cancer. Free Radic Biol Med 2011, 50(10):1344-1354.
224. Park SK, Sanders BG, Kline K: Tocotrienols induce apoptosis in breast cancer cell lines via an endoplasmic reticulum stress-dependent increase in extrinsic death receptor signaling. Breast Cancer Res Treat 2010, 124(2):361-375.
225. Shah S, Sylvester PW: Tocotrienol-induced caspase-8 activation is unrelated to death receptor apoptotic signaling in neoplastic mammary epithelial cells. Exp Biol Med (Maywood) 2004, 229(8):745-755.
226. Shah S, Gapor A, Sylvester PW: Role of caspase-8 activation in mediating vitamin E-induced apoptosis in murine mammary cancer cells. Nutr Cancer 2003, 45(2):236-246.