**6. Mechanism of action of tocotrienols in cancer prevention and treatment**

Tocotrienols possess several mechanisms which are deemed to be anticarcinogenic i.e., including anti-inflammatory, anti-proliferative, anti-survival, anti-angiogenic properties. These properties are mediated through the regulation of several signalling pathways which influence the process of carcinogenesis [24].

Tocotrienols affect anti-inflammatory activities by repressing COX-2, hypoxiainducible factor-1 (HIF-1), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), and interleukin (IL)-1, IL-6, and IL-8. There are convincing suggestions that the anticarcinogenic activity of tocotrienols is mediated mainly by the repression of two main transcription factors, NF-κB and STAT3 [24].

Tocotrienols were found to suppress the tumour necrosis factor-alpha (TNF-α) induced NF-κB activation, resulting in the downregulation of its associated gene products which are responsible for the survival of cells, which includes inhibitors of apoptosis proteins (IAP)-1, −2, B-cell lymphoma 2 (Bcl-2), B- cell lymphoma-extra

large (Bcl-xL), cellular FLICE-like inhibitory protein (cFLIP), X-linked inhibitor of apoptosis (XIAP), survivin etc. [65]. The regulators of STAT3 e.g., Src kinase, Janus kinase (JAK) 1and JAK2 are all inhibited by tocotrienols, which eventually resulted in the downregulation of STAT3. Tocotrienols suppress the growth of cancer cells by means of downregulation of 3- hydroxy-3-methylglutaryl coenzyme A reductase [24], cyclin-dependent kinases (CDK)-2, −4, −6, c-Jun, c-Myc, mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, Wnt/β-catenin, amongst others [65]. Tocotrienols have also been reported to facilitate the arrest of cellular growth and apoptosis through activation of CDK inhibitors (p21, p27, p53), caspase-3, −8, 9, Bcl-2-associated X (Bax) and enhancing cleavage of Bid, Apaf-1, Fas, etc. [54, 66]. Furthermore, tocotrienols were found to inhibit angiogenesis in cancer through downregulation of angiopoietin-1 fibroblast growth factor (FGF), metalloproteinase-9 (MMP-9), TNF-α, and vascular endothelial growth factor (VEGF) [16, 24, 63].
