Sesamin manifests chemopreventive effects through the suppression of NF-kappa B-regulated cell survival, proliferation, invasion, and angiogenic gene products.
Agents that are safe, affordable, and efficacious are urgently needed for the prevention of chronic diseases such as cancer. Sesamin, a lipid-soluble lignan, is one such agent that belongs to a class of phytoestrogens, isolated from sesame (Sesamum indicum), and has been linked with prevention of hyperlipidemia, hypertension, and carcinogenesis through an unknown mechanism. Because the transcription factor NF-kappaB has been associated with inflammation, carcinogenesis, tumor cell survival, proliferation, invasion, and angiogenesis of cancer, we postulated that sesamin might mediate its effect through the modulation of the NF-kappaB pathway. We found that sesamin inhibited the proliferation of a wide variety of tumor cells including leukemia, multiple myeloma, and cancers of the colon, prostate, breast, pancreas, and lung. Sesamin also potentiated tumor necrosis factor-alpha-induced apoptosis and this correlated with the suppression of gene products linked to cell survival (e.g., Bcl-2 and survivin), proliferation (e.g., cyclin D1), inflammation (e.g., cyclooxygenase-2), invasion (e.g., matrix metalloproteinase-9, intercellular adhesion molecule 1), and angiogenesis (e.g., vascular endothelial growth factor). Sesamin downregulated constitutive and inducible NF-kappaB activation induced by various inflammatory stimuli and carcinogens, and inhibited the degradation of IkappaBalpha, the inhibitor of NF-kappaB, through the suppression of phosphorylation of IkappaBalpha and inhibition of activation of IkappaBalpha protein kinase, thus resulting in the suppression of p65 phosphorylation and nuclear translocation, and NF-kappaB-mediated reporter gene transcription. The inhibition of IkappaBalpha protein kinase activation was found to be mediated through the inhibition of TAK1 kinase. Overall, our results showed that sesamin may have potential against cancer and other chronic diseases through the suppression of a pathway linked to the NF-kappaB signaling.
Harikumar
Kuzhuvelil B
KB
Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Sung
Bokyung
B
Tharakan
Sheeja T
ST
Pandey
Manoj K
MK
Joy
Beena
B
Guha
Sushovan
S
Krishnan
Sunil
S
Aggarwal
Bharat B
BB
D042501:Angiogenic Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004149:Dioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D017705:Lignans / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D012715:Sesame Oil / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D042501:Angiogenic Proteins; D000970:Antineoplastic Agents; D000975:Antioxidants; D004149:Dioxoles; D006131:Growth Inhibitors; D017705:Lignans; D016328:NF-kappa B; D012715:Sesame Oil; C054125:sesamin
J Biol Chem. 2004 Feb 6;279(6):4750-9
14630924
J AOAC Int. 2006 Jul-Aug;89(4):1174-81
16915861
Anticancer Res. 1992 Jul-Aug;12(4):1259-65
1386971
Cancer Sci. 2007 Sep;98(9):1447-53
17640297
J Nutr. 2006 Apr;136(4):906-12
16549449
Phytother Res. 2001 Aug;15(5):441-3
11507740
Biochem Pharmacol. 2008 Feb 15;75(4):907-13
18036510
Carcinogenesis. 2000 May;21(5):871-9
10783306
Neuroreport. 2003 Oct 6;14(14):1815-9
14534426
Atherosclerosis. 1996 Apr 26;122(1):135-36
8724120
Blood. 2003 Feb 1;101(3):1053-62
12393461
J Neurosci Res. 2003 Oct 1;74(1):123-33
13130514
J Exp Med. 1991 Nov 1;174(5):1275-8
1940805
Int Arch Allergy Immunol. 1997 Oct;114(2):153-60
9338609
EMBO J. 1991 Aug;10(8):2247-58
2065663
J Nutr. 1992 Dec;122(12):2440-6
1453229
Clin Exp Pharmacol Physiol Suppl. 1995 Dec;22(1):S310-2
9072406
Clin Cancer Res. 2009 Jan 15;15(2):425-30
19147746
Cell. 1996 Jan 26;84(2):299-308
8565075
Prostaglandins Leukot Essent Fatty Acids. 1999 Dec;61(6):347-52
10718106
Am J Clin Nutr. 2008 Jun;87(6):1723-9
18541561
J Lipid Res. 1991 Apr;32(4):629-38
1856608
J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):87-91
19352068
J Immunol. 2007 Feb 15;178(4):2507-16
17277159
Oncol Rep. 2000 Nov-Dec;7(6):1213-6
11032916
J Nutr. 2005 May;135(5):1056-62
15867281
Mol Pharmacol. 2007 Jun;71(6):1703-14
17387141
Lipids. 1991 Jul;26(7):512-6
1943494
Cancer Cell. 2004 Sep;6(3):203-8
15380510
Int J Mol Med. 2000 Jul;6(1):43-6
10851264
J Biol Chem. 2005 Dec 30;280(52):43056-63
16260783
J Biol Chem. 1999 Mar 19;274(12):7724-31
10075662
Methods Enzymol. 2000;319:585-602
10907546
Arch Pharm Res. 2004 Oct;27(10):1043-7
15554262
Biol Pharm Bull. 1995 Jul;18(7):1016-9
7581242
Life Sci. 2005 Oct 14;77(22):2794-803
15996687
Cell. 2002 Apr;109 Suppl:S81-96
11983155
Annu Rev Immunol. 1998;16:225-60
9597130
J Nutr Sci Vitaminol (Tokyo). 1998 Oct;44(5):715-22
9919491
J Nutr. 2006 May;136(5):1270-5
16614415
Biochem Pharmacol. 2004 Sep 15;68(6):1071-80
15313403
Immunol Lett. 2005 Feb 15;97(1):101-6
15626481