ABSTRACT
The tumor-suppressive activity of tocotrienols, vitamin E molecules with an unsaturated isoprenoid side chain, has been extensively reviewed in the previous edition of this book (Mo and Elson 2008). Tocotrienols at physiologically attainable concentrations suppress the proliferation of tumor cells derived from breast, liver, prostate, skin, colon, blood, lung, lymph gland, cervix, and nerve. Tocotrienol-mediated growth suppression is attributed to cell cycle arrest, mostly at the G1 phase of cell cycle, and apoptosis. Signaling pathways associated with promoting cell cycle progression, growth, and survival, including mitogen-activated protein kinases (MAPK), Ras, RhoA, Raf/MAPK kinase (MEK)/extracellular signal-regulated kinases (ERK), c-Jun, c-myc, cyclin D/cdk4, protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), Akt, IκB kinase (IKK), IκB, nuclear factor κB (NFκB), c-Jun N-terminal kinase (JNK), Bcl-2, Bcl-xL, COX-2, matrix metalloproteinases (MMP), vascular endothelial growth factor (VEGF), FLIP, and telomerase, are suppressed by tocotrienols. On the other hand, signaling activities supporting growth arrest and apoptosis, including p21cip1WAF1, transforming growth factor-β (TGF-β), p53, Fas, Bax, Apaf-1, caspases, and Bid fragmentation, are activated by tocotrienols. Animal models with chemically initiated carcinogenesis and implanted tumors con•rmed the in vitro tumor-suppressive activity of tocotrienols. Differing from statins, the nondiscriminant competitive inhibitors of 3-hydroxy-3-methyglutaryl coenzyme A (HMG CoA)
10.1 Introduction .......................................................................................................................... 135 10.2Tumor-Suppressive Activity of Tocotrienols In Vitro........................................................... 136 10.3Tumor-Suppressive Activity of Tocotrienols In Vivo............................................................ 138 10.4Antioxidant-Independent Mechanism of Action.................................................................. 139 10.5Dysregulated HMG CoA Reductase in Tumors Supports Growth....................................... 140 10.6 Tocotrienols Suppress HMG CoA Reductase and Downstream Growth-Supportive
Cell Signaling....................................................................................................................... 141 10.7Potential of Tocotrienols in Adjuvant Therapy..................................................................... 142 10.8Summary.............................................................................................................................. 143 Acknowledgments.......................................................................................................................... 144 References ...................................................................................................................................... 144
reductase, tocotrienols are downregulators of the activity of HMG CoA reductase. Dysregulation of HMG CoA reductase in tumors offers a unique target for tumor-speci•c intervention. Recent literature continues to support the potential of tocotrienols as tumor-targeted agents in cancer chemoprevention and/or therapy.
