Publications
Synergistic antiproliferative effects of gamma-tocotrienol and statin treatment on mammary tumor cells
Wali VB, Sylvester PW.
Lipids. 2007 Dec;42(12):1113-23. Epub 2007 Aug 14.
Statins are potent inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase and display anticancer activity, but their clinical use is limited by their high-dose toxicity. Similarly, gamma-tocotrienol, an isoform of vitamin E, also reduces HMGCoA reductase activity and displays potent anticancer activity. Studies were conducted to determine if combined low dose treatment of gamma-tocotrienol with individual statins resulted in a synergistic antiproliferative effect on neoplastic mouse +SA mammary epithelial cells. Treatment with 3-4 microM gamma-tocotrienol or 2-8 microM simvastatin, lovastatin or mevastatin alone resulted in a significant decrease, whereas treatment with 10-100 microM pravastatin had no effect on +SA cell growth. However, combined treatment of subeffective doses (0.25 or 10 microM) of individual statins with 0.25-2.0 microM gamma-tocotrienol resulted in a dose-responsive synergistic inhibition in +SA cell proliferation. Additional studies showed that treatment with subeffective doses of individual statins or gamma-tocotrienol alone had no effect, whereas combined treatment of these compounds resulted in a relatively large decrease in intracellular levels of phosphorylated (activated) MAPK, JNK, p38, and Akt. These findings strongly suggest that combined low dose treatment of gamma-tocotrienol with individual statins may have potential value in the treatment of breast cancer without causing myotoxicity that is associated with high dose statin treatment.
Chemical reactivities and physical effects in comparison between tocopherols and tocotrienols: Physiological significance and prospects as antioxidants
Yoshida Y, Saito Y, Jones LS, Shigeri Y.
J Biosci Bioeng. 2007 Dec;104(6):439-45.
Vitamin E is a generic term for all tocopherol and tocotrienol derivatives. The most abundant and active form of vitamin E isoforms in vivo is alpha-tocopherol, but recently the roles of other forms of vitamin E have received renewed attention. In this review, we summarize the differences among alpha-, beta-, gamma-, delta-tocopherols and tocotrienols specifically regarding the following points; (i) their radical-scavenging efficacies and chemical reactivity with metal ions in solution, (ii) their physical effects at the liposomal membrane interior, and (iii) their protective effects against cell toxicity. Moreover, the physiological significance and future prospects for using vitamin E, especially tocotrienols, for the prevention and treatment of disease are discussed.
Tocotrienol levels in adipose tissue of benign and malignant breast lumps in patients in Malaysia
Nesaretnam, K., Gomez, P. A.,Selvaduray, K. R.,Razak, G. A.
Asia Pac J Clin Nutr, 2007;16(3):498-504
Data on dietary exposure to vitamin E by plasma or adipose tissue concentrations of alpha-tocopherol (alpha-T) in observational studies have failed to provide consistent support for the idea that alpha-T provides women with any protection from breast cancer. In contrast, studies indicate that alpha, gamma, and delta-tocotrienols but not alpha-T have potent anti-proliferative effects in human breast cancer cells. Our aim was to investigate whether there was a difference in tocopherol and tocotrienol concentrations in malignant and benign adipose tissue, in a Malaysian population consuming predominantly a palm oil diet. The study was undertaken using fatty acid levels in breast adipose tissue as a biomarker of qualitative dietary intake of fatty acids. The major fatty acids in breast adipose tissue of patients (benign and malignant) were oleic acid (45-46%), palmitic (28-29%) and linoleic (11-12%). No differences were evident in the fatty acid composition of the two groups. There was a significant difference (p=0.006) in the total tocotrienol levels between malignant (13.7 +/- 6.0 microg/g) and benign (20+/-6.0 microg/g) adipose tissue samples. However, no significant differences were seen in the total tocopherol levels (p=0.42) in the two groups. The study reveals that dietary intake influences adipose tissue fatty acid levels and that adipose tissue is a dynamic reservoir of fat soluble nutrients. The higher adipose tissue concentrations of tocotrienols in benign patients provide support for the idea that tocotrienols may provide protection against breast cancer.
Vitamin E and apoptosis
Sylvester PW.
Vitam Horm. 2007;76:329-56.
Vitamin E is a generic term that refers to a family of compounds that is further divided into two subgroups called tocopherols and tocotrienols. All natural forms of tocopherols and tocotrienols are potent antioxidants that regulate peroxidation reactions and controls free radical production within the body. However, it is now firmly established that many of the biological actions mediated by individual vitamin E isoforms are not dependent on their antioxidant activity. Furthermore, synthetic ether derivatives of vitamin E that no longer possess antioxidant activity also display a wide range of biological activities. One of the most intriguing therapeutic applications for natural vitamin E and vitamin E derivatives currently being investigated is their use as anticancer agents. Specific forms of vitamin E display potent apoptotic activity against a wide range of cancer cell types, while having little or no effect on normal cell function or viability. Experimental studies have also determined that the intracellular mechanisms mediating the apoptotic effects of specific vitamin E compounds display great diversity in different types of caner cells and has been found to restore multidrug resistant tumor cells sensitivity to chemotherapeutic agents. These findings strongly suggest that some natural and synthetic analogues of vitamin E can be used effectively as anticancer therapy either alone or in combination to enhance the therapeutic efficacy and reduce toxicity of other anticancer agents.
Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolemic subjects
James M. Roza, CN; Zheng Xian-Liu, PhD; Najla Guthrie
Altern Ther Health Med. 2007 Nov-Dec;13(6):44-8
Context • Preliminary studies have suggested that both citrus flavonoids and palm tocotrienols reduce cholesterol levels in laboratory animals.
Objective • To examine the effect of these nutrients in combination on blood levels of cholesterol and related cardiovascular disease risk factors.
Design • Two open-label studies and 1 double-blind study are reported.
Setting • Outpatient clinical research setting.
Patients • Three groups (n=10, n=10, n=120) of hypercholesterolemic men and women (cholesterol levels >230 mg/dL) between the ages of 19 and 65 years were recruited.
Intervention • Subjects were randomized to consume either 270 mg citrus flavonoids plus 30 mg tocotrienols (S) or placebo (P) daily for a period of 4 weeks (group 1 [G1] and group 2[G2]) or 12 weeks (group 3 [G3]).
Main Outcome Measures • Measurements of fasting levels of blood cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were made at baseline and 4 weeks (all groups) and at 8 weeks and 12 weeks (G3).
Results • Daily treatment with S significantly improved cardiovascular parameters compared to P in all groups. Significant reductions were shown in total cholesterol (20%-30%), LDL (19%-27%), apolipoprotein B (21%), and triglycerides (24%-34%). HDL levels remained unchanged in G1 and G2 but increased 4% (nonsignificant) in G3 and was accompanied by a significant increase in apolipoprotein A1 (5%).
Protection of cerebellar granule cells by tocopherols and tocotrienols against methylmercury toxicity
Shichiri M, Takanezawa Y, Uchida K, Tamai H, Arai H.
Brain Res. 2007 Nov 28;1182:106-15.
Excessive free radical formation has been implicated as one of the causative factors in neurotoxic damage associated with variety of metals, including methylmercury (MeHg). Although the mechanisms associated with MeHg-dependent neurotoxicity remains are unclear, it is known that MeHg leads to neurotoxicity in cerebellar granule cells (CGCs). In vitro exposure of murine CGC primary cultures to MeHg resulted in time- and concentration-dependent cell death. The present study was designed to assess the effect of fat-soluble antioxidant tocopherols and tocotrienols (unsaturated vitamin E) on MeHg-induced neurotoxicity using cultured CGCs. Significant protection from MeHg-induced neuronal cell death was observed with both tocopherols and tocotrienols. Moreover, we observed that tocotrienols are multi-fold more potent than tocopherols in protecting CGCs against MeHg neurotoxicity. At micromolar concentration, tocotrienols, but not tocopherols, showed complete protection by an antioxidant mechanism. Similarly, tocopherols and tocotrienols showed a protective effect on CGCs migration against MeHg-toxicity. These results suggested that oxidative events may contribute to MeHg toxicity in isolated cerebellar granule neurons, and that tocotrienols are potent supplements for pharmacological protection of the developing brain exposed to MeHg.
Vitamin E and mast cells
Zingg JM.
Vitam Horm. 2007;76:393-418.
Mast cells play an important role in the immune system by interacting with B and T cells and by releasing several mediators involved in activating other cells. Hyperreactivity of mast cells and their uncontrolled accumulation in tissues lead to increased release of inflammatory mediators contributing to the pathogenesis of several diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and allergic disorders such as asthma and allergic rhinitis. Interference with mast cell proliferation, survival, degranulation, and migration by synthetic or natural compounds may represent a preventive strategy for the management of these diseases. Natural vitamin E covers a group of eight analogues-the alpha-, beta-, gamma-, and delta-tocopherols and the alpha-, beta-, gamma-, and delta-tocotrienols, but only alpha-tocopherol is efficiently retained by the liver and distributed to peripheral tissues. Mast cells preferentially locate in the proximity of tissues that interface with the external environment (the epithelial surface of the skin, the gastrointestinal mucosa, and the respiratory system), what may render them accessible to treatments with inefficiently retained natural vitamin E analogues and synthetic derivatives. In addition to scavenging free radicals, the natural vitamin E analogues differently modulate signal transduction and gene expression in several cell lines; in mast cells, protein kinase C, protein phosphatase 2A, and protein kinase B are affected by vitamin E, leading to the modulation of proliferation, apoptosis, secretion, and migration. In this chapter, the possibility that vitamin E can prevent diseases with mast cells involvement by modulating signal transduction and gene expression is evaluated.
Vitamin E: Inflammation And Atherosclerosis
U. Singh and S. Devaraj
Vitam Horm. 2007;76:519-49
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the western world with its incidence increasing lately in developing countries. Several lines of evidence support a role for inflammation in atherogenesis. Hence, dietary micronutrients having anti-inflammatory properties may have a potential beneficial effect with regard to CVD. Vitamin E is a potent antioxidant with anti-inflammatory properties. It comprises eight diferent isoforms: four tocopherols (T) (α, β, γ, and δ) and four tocotrienols (T3) (α, β, γ, and δ). A wealth of data is available for the preventive efficacy of alpha-T. alpha-T supplementation in human subjects and animal models has been shown to be antioxidant and antiinflammatory in terms of decreasing C-reactive protein (CRP) and release of proinflammatory cytokines, the chemokine IL-8 and PAI-1 levels especially at high doses. Gamma-T is effective in decreasing reactive nitrogen species and also appears to have antiinflammatory properties; however, there are scanty data examining pure gamma-T preparations. Furthermore, tocotrienols (α and γ) also have implications for prevention of CVD; however, there are conflicting and insuffcient data in the literature with regards to their potency. In this chapter, we have gathered recent emerging data on alpha T specifically and also have given a composite view of gamma-T and tocotrienols especially with regards to their effect on inflammation as it relates to CVD.
In Vivo Angiogenesis is Suppressed by Unsaturated Vitamin E, Tocotrienol
Nakagawa K, Shibata A, Yamashita S, Tsuzuki T, Kariya J, Oikawa S, Miyazawa T.
J Nutr. 2007 Aug;137(8):1938-43.
Antiangiogenic therapy using drugs and food components is a recognized strategy for the prevention of various angiogenesis-mediated disorders such as tumor growth, diabetic retinopathy, and rheumatoid arthritis. Our preliminary cell culture studies, using both bovine aortic endothelial cells and human umbilical vein endothelial cells (HUVEC) on screening for food-derived antiangiogenic compounds, showed tocotrienol (T3), an unsaturatedversion of vitamin E, to be a potential angiogenic inhibitor. We therefore investigaged the in vivo antiangiogenic properties of T3 using 2 well-characterized angiogenic models [mouse dorsal air sac (DAS) assay and the chick embryo chorioallantoic membrane (CAM) assay]. In the DAS assay, the increased neovascularization (angiogenesis index, 4.8 +/- 0.6) in tumor cell-implanted mice was suppressed (angiogenesis index, 2.7 +/- 0.6) by dietary supplementation of 10 mg T3-rich oil/d (equivalent to 4.4 mg T3/d). In the CAM assay, T3 (500-1000 microg/egg) inhibited new blood vessel formation on the growing CAM and increased the frequency of avascular zone (36-50%). To evaluate the antiangiogenic mechanism, we conducted cell-culture studies and found that T3 significantly reduced fibroblast growth factor -induced proliferation, migration, and tube formation inHUVEC (P < 0.05), with delta-T3 having the highest activity. Western blot analysis revealed that delta-T3 suppressed the phosphorylation of phosophoinositide-dependent protein kinase (PDK) and Akt, and increased the phosphorylation of apoptosis signal-regulating kinase and p38 infibroblast growth factor-treated HUVEC, indicating that the antiangiogenic effects of T3 are associated with changes in growth factor-dependent phosphatidylinositol-3 kinase /PDK/Akt signaling as well as induction of apoptosis in endothelial cells. Our findings suggest that T3 has potential as a therapeutic dietary supplement for preventing angiogenic disorders, and therefore future clinical study will be required to evaluate the efficacy and safety of T3.