Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways

Yap, W. N.,Chang, P. N.,Han, H. Y.,Lee, D. T.,Ling, M. T.,Wong, Y. C.,Yap, Y. L.

Br J Cancer, 2008; 99(11):1832-41

Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

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Dietary antioxidants as potential pharmacological agents for ischemic stroke

Cherubini A, Ruggiero C, Morand C, Lattanzio F, Dell'aquila G, Zuliani G, Di Iorio A, Andres-Lacueva C.

Curr Med Chem. 2008;15(12):1236-48.

Acute ischemic stroke is a leading cause of death and severe disability in industrialised countries and also in many developing countries. An excessive amount of free radicals is generated during cerebral ischemia, which significantly contributes to brain damage. Therefore, an increasing interest has been devoted to the potential benefits of antioxidant compounds in ischemic stroke patients. In this review, we examined the most relevant observational studies concerning the relationship between dietary antioxidants and ischemic stroke as well as clinical trials investigating the effects of single or multiple antioxidant supplementation in the prevention or treatment of acute ischemic stroke. Furthermore, we reviewed the most promising antioxidant compounds, i.e. dehydroascorbic acid, alpha-tocotrienol, gamma-tocopherol, flavonoids, resveratrol and gingko biloba, tested in animal models of acute ischemic stroke. Finally, we carefully evaluated the reasons for the discrepancy between experimental and clinical studies, and provided recommendations to improve the translation of the results obtained in animal models to patients with acute ischemic stroke.

Tocotrienol inhibits secretion of angiogenic factors from human colorectal adenocarcinoma cells by suppressing hypoxia-inducible factor-1alpha

Shibata A, Nakagawa K, Sookwong P, Tsuduki T, Tomita S, Shirakawa H, Komai M, Miyazawa T.

J Nutr. 2008 Nov;138(11):2136-42.

Tocotrienol (T3), unsaturated vitamin E, has recently gained considerable attention as a potent antiangiogenic agent minimizing tumor growth, the exact intracellular mechanisms of which remain poorly understood. Because hypoxia-inducible factor-1alpha (HIF-1alpha), its downstream target vascular endothelial growth factor (VEGF), and other angiogenic factors such as interleukin-8 (IL-8) and cyclooxygenase 2 (COX-2) play critical roles in neovascularization, we tested the hypothesis that the inhibitory effect of T3 on tumor angiogenesis is via regulation of these angiogenic factors. We used 2 cancer cell lines, human colorectal adenocarcinoma cells (DLD-1) and human hepatoma cells (HepG2). T3 isomers (2 micromol/L) inhibited hypoxia-induced VEGF secretion from DLD-1, with delta-T3 showing potent inhibition. Delta-T3 suppressed hypoxia-induced VEGF and IL-8 expression in DLD-1 at both mRNA and protein levels, and we found the inhibitory mechanism of delta-T3 by reducing HIF-1alpha protein expression or increasing HIF-1alpha degradation. Also, delta-T3 (2 micromol/L) did not affect hypoxia-induced COX-2 mRNA expression; however, delta-T3 tended to suppress (P = 0.044) hypoxia-induced COX-2 protein expression, implying a possible post-transcriptional mechanism by delta-T3. Overall, our results confirmed that T3 has an inhibitory effect on angiogenic factor secretion from cancer cells and revealed the possible mechanisms, providing new information about the antiangiogenic effects of T3.

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Vitamin E in nature is comprised of a family of tocopherols and tocotrienols. The most studied of these is alpha-tocopherol (alpha-TOH), because this form is retained within the body, and vitamin E deficiency is corrected with this supplement. alpha-TOH is a lipid-soluble antioxidant required for the preservation of cell membranes, and it potentially acts as a defense against oxidative stress. Many studies have investigated the metabolism, transport, and efficacy alpha-TOH in the prevention of sequelae associated with cardiovascular disease (CVD). Supplementation with vitamin E is considered to provide health benefits against CVD through its antioxidant activity, the prevention of lipoprotein oxidation, and the inhibition of platelet aggregation. However, the results from large prospective, randomized, placebo-controlled clinical trials with alpha-TOH have been largely negative. A recent meta-analysis suggests that alpha-TOH supplements may actually increase all-cause mortality; however, the mechanism for this increased risk is unknown. In vitro studies performed in human cell cultures and animal models suggest that vitamin E might increase the hepatic production of cytochrome P450s and MDR1. Induction of CYP3A4 or MDR1 by vitamin E could potentially lower the efficacy of any drug metabolized by CYP3A4 or MDR1. Other possibilities include an adverse effect of alpha-TOH on blood pressure in high-risk populations. Because of the wide popularity and use of vitamin E supplements, further research into potential adverse effects is clearly warranted.

Tocopherol and tocotrienol compositions were studied in 175 genotypes of different wheat types grown under similar conditions to screen for natural diversity. The main focus was on bread wheats, including 130 and 20 winter and spring types, respectively. The average total content of tocopherols and tocotrienols was 49.4 microg/g of dm, with a range of 27.6-79.7 microg/g of dm, indicating a 2.9-fold variation among genotypes. Beta-tocotrienol and alpha-tocopherol were the major vitamers, and in general there were more tocotrienols than tocopherols. In the early cultivated forms of wheat the proportion of tocotrienols was especially high, at >or=62.5%. In conclusion, there was a large variation in total tocopherol and tocotrienol contents in bread wheats and this, along with the high proportions of tocotrienols in other types of wheat, demonstrates the great genetic potential of genotypes to be exploited by plant breeders.