Sesamin Manifests Chemopreventive Effects through the Suppression of NF-κB-Regulated Cell Survival, Proliferation, Invasion, and Angiogenic Gene Products

Agents that are safe, affordable and efficacious are urgently needed for 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-κB 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 NF-κB pathway. We found that sesamin inhibited the proliferation of wide variety of tumor cells including leukemia, multiple myeloma, and cancers of the colon, prostate, breast, pancreas and lung. Sesamin also potentiated TNF-α induced apoptosis and this correlated with suppression of gene products linked to cell survival (e.g.; Bcl-2 and survivin), proliferation (e.g.; cyclin D1), inflammation (e.g.; COX-2), invasion (e.g.; MMP-9, ICAM-1) and angiogenesis (e.g.; VEGF). Sesamin downregulated constitutive and inducible NF-κB activation induced by various inflammatory stimuli and carcinogens; and inhibited degradation of IκBα, the inhibitor of NF-κB through the suppression of phosphorylation of IκBα and inhibition of activation of IκBα protein kinase (IKK); thus resulting in the suppression of p65 phosphorylation and nuclear translocation, and NF-κB-mediated reporter gene transcription. The inhibition of IKK activation was found to be mediated through the inhibition of TAK1 kinase. Overall our results demonstrated that sesamin may have potential against cancer and other chronic diseases through the suppression of pathway linked to the NF-κB signaling.