Cancer Research
An Overview
In addition to its superior antioxidant, hypocholesterolemic, and anti-thrombotic activities, tocotrienol has repeatedly been shown to have anti-tumor benefits. Some researchers attribute these anti-cancer effects to tocotrienolís antioxidant activity34, HMG-CoA reductase downregulation and/or degradation3,35, caspase-3 apoptotic pathways36, and vascular endothelial growth factor (VEGF) inhibition37. Tocotrienols, but not tocopherols (in particular alpha-tocopherol), have repeatedly been shown to inhibit proliferation and induce cell death in cancer cells, and cells with the greatest degree of malignancy are most sensitive to the apoptotic action of tocotrienol36,38,39.
Possible Mechanisms of Cancer Inhibition by Tocotrienol
Antioxidant Potency: Reduction of lipid peroxidation and formation of reactive products or inhibition of formation of mutagenic nitric oxide species prevent DNA mutations that increase the risk of cancer7. Also, tocotrienol may inhibit cancer by the quenching of free radicals, or increase the efficacy of anti-tumor actions by strengthening the immune system40.
Apoptosis Activation: Tocotrienol may stimulate death receptors such as tumor necrosis factor (TNF) and Fas, which leads to activation of caspases, including caspase-8, -9, and – 3. Activation of these caspases mediates the various cytoplasmic and nuclear events associated with apoptosis9. A recent study showed that gamma-tocotrienol stimulates a rise in caspase-8, -9, and -3, thereby inducing apoptosis4.
Cholesterol Downregulation: Tocotrienols suppress the intermediates (farnesyl pyrophosphate and geranyl geranyl pyrophosphate) in the mevalonate synthesis pathway that tumor tissues are derived from35. This relationship between the mevalonate pathway and tumor tissues is due to an anomaly in tumor growth, where the HMG-CoA reductase is resistant to sterol-feedback. However, the tumor HMG-CoA reductase retains high sensitivity to isoprenoid-mediated regulation42. In this way, tocotrienols reduce Ras, arrest cells in the G1 phase, and initiate cellular apoptosis43. In an in vivo and in vitro study that proposes this mechanism of cancer inhibition, duration of host survival was increased and growth of cancerous cells inhibited by 50% using 10umol/L of delta- tocotrienol44.
Angiogenesis Inhibition: Recent studies showed that tocotrienols but not tocopherols inhibit angiogenesis, an indispensable step in tumor growth. Vascular endothelial growth factor (VEGF) regulates angiogenesis by binding to VEGF receptor (VEGFR) in endothelial cells. Tocotrienol may downregulate VEGFR, therefore blocking intracellular signaling of VEGF and inhibiting angiogenesis37. In addition, tocotrienol inhibits the proliferation and formation of tubes by bovine aortic endothelial cells, where delta- tocotrienol had the strongest inhibitory activity45. Since angiogenesis is essential to tumor growth, its inhibition may likely prevent cancer metastasis.
Tocotrienol and Breast Cancer
Breast cancer is the leading cancer among white and African American women, with an approximate 275,000 new cases and estimated 41,000 deaths each year in the United States. Tocotrienol-rich fractions (TRF) containing 43% desmethyl tocotrienols inhibited the proliferation of human breast cancer cells, whereas alpha-tocopherol had no effect46. Another study found that tocotrienols inhibit breast cancer irrespective of estrogen receptor status, with gamma- and delta-tocotrienol being the most potent inhibitors47. Since gamma- and delta-tocotrienol have repeatedly been shown to be the strongest inhibitors of cancer, it may be of great advantage to use desmethyl tocotrienols in their purest form during treatment. Unfortunately, dietary vitamin E only contains a very small amount of desmethyl tocotrienols (~10%), and 90% tocopherols, which have no effect in the treatment of cancer48. The safety of tocotrienols has been reported in a recent study where no or only low levels of apoptosis occurred in immortalized non-tumorigenic breast epithelial cells49.
Tocotrienol and Other Cancers
Pancreatic Cancer: Anti-tumorigenic effects of delta-T3 on human pancreatic cancer were shown in vitro and in vivo (Xenografts in mice). Here, delta-tocotrienol inhibited pancreatic tumor growth, blocked malignant transformation, induced apoptosis in vitro, and accumulated in the pancreas 10x more than in the liver and tumor. The preferred composition was a preparation containing delta-tocotrienol and/or gamma-tocotrienol, and free of alpha-tocotrienol, beta-tocotrienol and tocopherol61. Prostate Cancer: Prostate cancer is the cause of ~30,000 deaths per year in the United States50. Tocotrienols and gamma-tocotrienol in particular, were shown to have inhibitory effects on several types of prostate cancer cell lines5.
Cervical Cancer: Palm oil tocotrienol, containing 70% of desmethyl tocotrienol, reduced cervical cancer in vitro52.
Lung Adenocarcinoma: An alpha-tocotrienol analogue decreased human lung adenocarcinoma by suppression of Ras and RhoA prenylation38.
Liver and Lung Carcinogenesis: A recent in vivo and in vitro study showed suppression of liver and lung carcinogenesis in mice. Delta-tocotrienol potently induced apoptosis and S phase arrest while increasing CYPIAI gene, a phase I enzyme39.
Tocotrienolís Protective Effect on Skin: Vitamin E, and in particular tocotrienol-rich fractions (TRF), have been shown to be superior protectors against environmental stressors such as UV-irradiation of the skin53. TRF has significantly higher potency than alpha-tocopherol, and is effective against protein oxidation and lipid peroxidation at low concetrations54,55. Normally, UV- irradiation destroys the antioxidants of the skin, but prior application of TRF to mouse skin preserved the vitamin E56. Also, the largest fraction of vitamin E was found in the subcutaneous layer of the skin, which shows that applied vitamin E penetrates rapidly through the skin57, and therefore combats oxidative stress induced by UV or ozone efficiently58.
Tocotrienol Use for Melanoma: Gamma- and delta-tocotrienol inhibited melanoma cells in vitro, and produced tumor retardation in mice with highly metastatic melanoma. Treatment also increased the duration of host survival44. Gamma- and delta-tocotrienol in combination with lovastatin are yet more potent in melanoma inhibition in vitro and in vivo59. Tocotrienol-mediated suppression of melanoma was independent of Ras and p53 functions, and occurred via apoptosis of tumor cells and cell arrest in the G1 phase of the cell cycle43.
