title: Sesamin manifests chemopreventive effects through the suppression of NF-kappa B-regulated cell survival, proliferation, invasion, and angiogenic gene products.
abstract: 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.
authors.affiliation: Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Kuzhuvelil B
authors.initials: KB
authors.lastname: Harikumar
authors.forename: Bokyung
authors.initials: B
authors.lastname: Sung
authors.forename: Sheeja T
authors.initials: ST
authors.lastname: Tharakan
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Pandey
authors.forename: Beena
authors.initials: B
authors.lastname: Joy
authors.forename: Sushovan
authors.initials: S
authors.lastname: Guha
authors.forename: Sunil
authors.initials: S
authors.lastname: Krishnan
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: 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
chemical_list: D042501:Angiogenic Proteins; D000970:Antineoplastic Agents; D000975:Antioxidants; D004149:Dioxoles; D006131:Growth Inhibitors; D017705:Lignans; D016328:NF-kappa B; D012715:Sesame Oil; C054125:sesamin
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