title: Metabolism of tocotrienols in animals and synergistic inhibitory actions of tocotrienols with atorvastatin in cancer cells.
abstract: Tocotrienols (T3s), members of the vitamin E family, exhibit potent anti-cancer, anti-oxidative, anti-inflammatory, and some other biological activities. To better understand the bioavailability and metabolism of T3s, T3s and their metabolites were identified in urine and fecal samples from mice on diet supplemented with mixed T3s using HPLC/electrochemical detection and liquid chromatography electrospray ionisation mass spectrometry (LC-ESI-MS). Whereas the short-chain metabolites carboxyethyl hydroxychromans (CEHCs) and carboxymethylbutyl hydroxychromans (CMBHCs) were the major metabolites of T3s, several new metabolites with double bonds were also identified. Similar to tocopherols, the majority of T3 metabolites were excreted as sulfate/glucuronide conjugates in mouse urine. The distribution of γ- and δ-T3 and γ-T3 metabolites were also determined in different organs as well as in urine and fecal samples from mice on diets supplemented with corresponding T3s. The synergistic anti-cancer actions of γ-T3 and atorvastatin (ATST) were studied in HT29 and HCT116 colon cancer cell lines. The combination greatly potentiated the ability of each individual agent to inhibit cancer cell growth and to induce cell cycle arrest and apoptosis. The triple combination of γ-T3, ATST, and celecoxib exhibited synergistic actions when compared with any double combination plus the third agent. Mechanistic studies revealed that the synergistic actions of γ-T3 and ATST could be attributed to their mediation of 3-hydroxy-3-methyl-glutaryl-CoA reductase, and the subsequent inhibition of protein geranylgeranylation. It remains to be determined whether such a synergy occurs in vivo.
authors: Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology and Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
authors: Zhihong
authors: Z
authors: Yang
authors: Mao-Jung
authors: MJ
authors: Lee
authors: Yang
authors: Y
authors: Zhao
authors: Chung S
authors: CS
authors: Yang
references: Int J Cancer. 2011 May 1;128(9):2182-91
references: 20617516
references: Free Radic Biol Med. 2010 Nov 1;49(8):1315-22
references: 20692332
references: Free Radic Biol Med. 1991;10(5):263-75
references: 1649783
references: J Agric Food Chem. 2010 Apr 28;58(8):4844-52
references: 20222730
references: Int J Cancer. 2010 Feb 15;126(4):852-63
references: 19626588
references: Biochemistry. 2002 Nov 19;41(46):13698-704
references: 12427032
references: J Biol Chem. 2007 Jan 5;282(1):809-20
references: 17114179
references: Gastroenterology. 2007 Jun;132(7):2518-32
references: 17570223
references: Biochem Cell Biol. 2005 Feb;83(1):86-95
references: 15746970
references: Biosci Biotechnol Biochem. 2002 Feb;66(2):398-403
references: 11999415
references: Asia Pac J Clin Nutr. 2008;17 Suppl 1:253-6
references: 18296349
references: Mol Nutr Food Res. 2008 Aug;52(8):921-9
references: 18481320
references: J Clin Biochem Nutr. 2010 Sep;47(2):148-54
references: 20838570
references: J Biol Chem. 1993 May 25;268(15):11230-8
references: 8388388
references: Mol Cell Biochem. 1997 May;170(1-2):131-7
references: 9144327
references: Cell Prolif. 2006 Dec;39(6):563-74
references: 17109639
references: Int J Oncol. 2008 Oct;33(4):851-9
references: 18813800
references: Chem Phys Lipids. 2003 Mar;123(1):63-75
references: 12637165
references: J Cell Mol Med. 2010 Oct;14(10):2506-18
references: 19799646
references: Exp Biol Med (Maywood). 2007 Apr;232(4):523-31
references: 17392488
references: Br J Nutr. 2009 Mar;101(6):810-5
references: 18702848
references: Am J Physiol Endocrinol Metab. 2009 Aug;297(2):E427-37
references: 19491296
references: Br J Nutr. 2008 Jun;99(6):1247-54
references: 18081943
references: J Atheroscler Thromb. 2010 Oct 27;17(10):1019-32
references: 20702976
references: Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20464-9
references: 19074288
references: J Biol Chem. 2006 Sep 1;281(35):25054-61
references: 16831864
references: J Nutr. 2009 May;139(5):884-9
references: 19297424
references: J Biol Chem. 2010 Oct 22;285(43):33520-33529
references: 20720018
references: Radiat Res. 2009 May;171(5):596-605
references: 19580495
references: Mol Nutr Food Res. 2010 May;54(5):669-78
references: 20306477
references: Mol Nutr Food Res. 2010 Mar;54(3):345-52
references: 19866471
references: Biochem Pharmacol. 2004 Jan 15;67(2):315-24
references: 14698044
references: Biochem Biophys Res Commun. 2006 Jul 28;346(2):447-53
references: 16762318
references: Exp Biol Med (Maywood). 2004 Sep;229(8):745-55
references: 15337828
references: Exp Biol Med (Maywood). 2005 Apr;230(4):235-41
references: 15792944
references: Life Sci. 2009 May 8;84(19-20):650-6
references: 19232361
references: Biomed Pharmacother. 2010 May;64(5):327-32
references: 19954924
references: J Nutr. 2002 Oct;132(10):3113-8
references: 12368403
references: Eur J Clin Nutr. 2011 Jan;65(1):63-9
references: 20859299
references: Br J Cancer. 2008 Dec 2;99(11):1832-41
references: 19002171