Tocotrienols belong to the vitamin E family of chemicals known to have potent anti-proliferative and apoptotic activities against a variety of cancer cells with little to no comparable influence on the normal cells. Whether tocotrienols control the expression of phase II antioxidant enzymes in the context of their anti-carcinogenic mechanisms has not been investigated. The present studies were performed to test whether the differential growth inhibition resulting from exposure to α-, γ- and δ-tocotrienols in estrogen receptor-positive human MCF-7 and estrogen receptor-negative MDA-MB-231 breast cancer cells might be accompanied by changes in phase II antioxidant enzymes. Cell proliferation and clonogenicity in both cell lines were significantly inhibited by γ- and δ-tocotrienols with little affect when cells were similarly exposed to α-tocotrienol, at doses up to 10 μM. The expression and activity of several antioxidant enzymes in 10 μM tocotrienol-treated cells were determined by Western blot and biochemical assays. In MDA-MB-231 cells, δ- was more active than α- or γ-tocotrienols in up-regulating glutathione peroxidase; however, the three tocotrienols had comparable activity in inducing thioredoxin. In MCF-7 cells, expression of quinone reductase 2 and thioredoxin was increased by γ- and δ-tocotrienols, whereas quinone reductase 1 was unaffected by exposure to the tocotrienols. The tocotrienols also did not affect the expression and activity of superoxide dismutase in both MCF-7 and MDA-MB-231 cells, but increased catalase activity concomitant with slight reduction in the catalase expression. In MDA-MB-231 cells, treatment by tocotrienols led to several fold increase of NRF2 expression marked by corresponding decrease in KEAP1 levels. By contrast, no significant change in NRF2 and KEAP1 levels was observed in MCF-7 cells. These studies demonstrate that different tocotrienols show distinct and selective activity in regulating the NRF2-KEAP1, in coordination with the induced expression of cytoprotective oxidative stress modulatory genes and regulation of proliferation in breast cancer cells.
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Protective effects of vitamin E analogs against carbon tetrachloride-induced fatty liver in rats
Yachi R, Igarashi O, Kiyose C.
J Clin Biochem Nutr. 2010 Sep;47(2):148-54. Epub 2010 Aug 6.
Recently, it has been reported that α-tocopherol (α-Toc) is effective for amelioration of liver damage. However, it is unknown whether other vitamin E analogs are effective. In this study, we investigated the effects of γ-tocopherol (γ-Toc) and tocotrienols (T3) in rats with fatty liver. Rats fed a vitamin E-deficient diet for four weeks were divided into eight groups: Control, carbon tetrachloride (CCl(4)), α-Toc, α-Toc + CCl(4), γ-Toc, γ-Toc + CCl(4), T3 mix, T3 mix + CCl(4). After a 24 h fast, the rats were administered 20 mg of each of the vitamin E analogs, respectively. Moreover, the CCl(4) group were given 0.5 ml/kg body weight corn oil preparation containing CCl(4) 6 h after vitamin E administration. We measured the activities of aspartate aminotransferase and alanine aminotransferase (ALT) in plasma, and the contents of triglyceride (TG), total cholesterol (T-Chol) and vitamin E analogs in the liver. Also, we determined the hepatic expression of mRNA for inflammatory cytokines. The liver TG content in the γ-Toc + CCl(4) and T3 mix + CCl(4) groups was decreased in comparison with the CCl(4) group. Moreover, ALT activity in the T3 mix + CCl(4) group was significantly lower than CCl(4) group. These findings suggest that γ-Toc and T3 are effective for amelioration of fatty liver.
Regulation of survival, proliferation, invasion, angiogenesis, and metastasis of tumor cells through modulation of inflammatory pathways by nutraceuticals
Gupta SC, Kim JH, Prasad S, Aggarwal BB.
Cancer Metastasis Rev. 2010 Sep;29(3):405-34.
Almost 25 centuries ago, Hippocrates, the father of medicine, proclaimed “Let food be thy medicine and medicine be thy food.” Exploring the association between diet and health continues today. For example, we now know that as many as 35% of all cancers can be prevented by dietary changes. Carcinogenesis is a multistep process involving the transformation, survival, proliferation, invasion, angiogenesis, and metastasis of the tumor and may take up to 30 years. The pathways associated with this process have been linked to chronic inflammation, a major mediator of tumor progression. The human body consists of about 13 trillion cells, almost all of which are turned over within 100 days, indicating that 70,000 cells undergo apoptosis every minute. Thus, apoptosis/cell death is a normal physiological process, and it is rare that a lack of apoptosis kills the patient. Almost 90% of all deaths due to cancer are linked to metastasis of the tumor. How our diet can prevent cancer is the focus of this review. Specifically, we will discuss how nutraceuticals, such as allicin, apigenin, berberine, butein, caffeic acid, capsaicin, catechin gallate, celastrol, curcumin, epigallocatechin gallate, fisetin, flavopiridol, gambogic acid, genistein, plumbagin, quercetin, resveratrol, sanguinarine, silibinin, sulforaphane, taxol, gamma-tocotrienol, and zerumbone, derived from spices, legumes, fruits, nuts, and vegetables, can modulate inflammatory pathways and thus affect the survival, proliferation, invasion, angiogenesis, and metastasis of the tumor. Various cell signaling pathways that are modulated by these agents will also be discussed.
Tocol composition was studied in 26 genotypes of wheat grown in one location for three years and in three other locations for one year. Special emphasis was placed on evaluating the variation of tocols within wheat genotypes and among various growing conditions. In general, both genetic and environmental effects had a strong impact on tocols in wheat genotypes. Because the growing locations and years differed considerably, greater variation due to the environment was found in this study than in earlier ones. Some of the genotypes were more sensitive to the impact of the environment, whereas others were relatively stable. Of the wheat genotypes with an average total tocol content of >or=55 microg/g of dry matter, five genotypes showed relatively low variation: Claire, Cadenza, Lynx, Atlas 66, and Disponent. These genotypes could be potential candidates for the breeding of stable and high-tocol content wheat cultivars.
Bone is a specialized connective tissue that functions as the load-bearing structure of the body. Free radicals may affect bone remodeling by regulating osteoclast activity in either the physiological or pathological condition. Vitamin E, a lipid-soluble antioxidant, has been demonstrated to offer protection against osteoporosis and to improve the bone material and structure of animal models. The aim of this study was to observe and compare the effects of alpha-tocopherol (alpha-tocopherol), delta-tocotrienol (delta-tocotrienol), and gamma-tocotrienol (gamma-tocotrienol) on the static and dynamic bone histomorphometric parameters in normal male rats. Thirty-two normal Sprague-Dawley male rats aged 3 months and weighing 200-250 g were randomly divided into four groups. The control group was supplemented with oral gavages of olive oil (vehicle), whereas the alpha-tocopherol, delta-tocotrienol, and gamma-tocotrienol groups were given oral gavages of 60 mg/kg alpha-tocopherol, delta-tocotrienol, and gamma-tocotrienol, respectively. The rats were injected twice with calcein to fluorochrome-label the bones. After 4 months of treatment, the rats were killed, and the left femurs were dissected out and prepared for bone histomorphometry. Both the static and dynamic parameters of the vitamin E-treated groups were better than those of the normal control group. Among the vitamin E-treated groups, the tocotrienol groups showed better histomorphometry results compared to the α-tocopherol group, with the γ-tocotrienol group demonstrating the best effects on both sets of parameters. We concluded that vitamin E can promote bone formation in normal rats, with gamma-tocotrienol being the most potent form of vitamin E.
The tocotrienol-rich fraction from rice bran enhances cisplatin-induced cytotoxicity in human mesothelioma H28 cells.
Nakashima K, Virgona N, Miyazawa M, Watanabe T, Yano T.
Phytother Res. 2010 Sep;24(9):1317-21.
Resistance to chemotherapy (chemoresistance) is a serious problem in malignant mesothelioma, a highly aggressive neoplasm. Gamma-tocotrienol (gamma-T3) can sensitize various cancerous cells to chemotherapeutic agents by inhibiting pathways that lead to treatment resistance. In this study, we investigated the modulating effect of tocotrienol-rich fraction (TRF) from rice bran, which is abundant in gamma-T3, on chemoresistance in human MM H28 cells. TRF treatment caused a marked reduction in the viability of H28 cells in a dose-dependent manner, while cisplatin treatment had no effect on the cells, indicating that H28 cells are resistant to cisplatin. A significant increase in cytotoxicity was observed in H28 cells treated with TRF, and this effect was enhanced by the combination treatment with cisplatin. The cytotoxic effect was closely related to the inhibition of phosphatidylinositol 3-kinase (PI3K)-AKT signaling. Inactivation of Akt signaling by TRF or the combination with cisplatin mitigated cisplatin-induced activation of Akt, resulting in reducing the chemoresistance H28 cells to cisplatin. Reduced cell viability and attenuated chemoresistance of the H28 cells against cisplatin were also observed following the use of a PI3K inhibitor, LY294002. These results suggest that the combination therapy of cisplatin with TRF is a plausible strategy for achieving tolerance for the chemotherapeutic agent in MM therapy.
Effect of δ-tocotrienol on melanin content and enzymes for melanin synthesis in mouse melanoma cells
Michihara A, Ogawa S, Kamizaki Y, Akasaki K.
Biol Pharm Bull. 2010;33(9):1471-6.
In the present study, we investigated the dose-dependent effect of delta-tocotrienol long term (48, 72 h) on the melanin content of cells treated with delta-tocotrienol, and whether cells treated with delta-tocotrienol for long a time show cytotoxicity. We also examined whether other enzymes responsible for melanin biosynthesis, tyrosinase-related protein-1 (TRP-1) and -2 (TRP-2), are involved in the decrease in melanin levels. Protein levels in cells treated with 25 or 50 microM delta-tocotrienol for 48 h or 72 h were similar to those in control cells. Melanin content decreased by 44 (25 microM delta-tocotrienol) to 50% (50 microM) at 48 h, and by 14 to 21% at 72 h, compared to control levels. Tyrosinase activity, amounts of tyrosinase and TRP-1 decreased dependent on dose : by 50 (25 microM delta-tocotrienol) to 75% (50 microM), 20 to 45% and 42 to 82% at 48 h, and by 25 to 50%, 75 to 80% and 78 to 77% at 72 h, respectively. Although the amount of TRP-2 increased by 20% on treatment with 25 microM delta-tocotrienol for 48 h, it decreased by 52% on treatment with 50 microM delta-tocotrienol for 48 h. The amount of TRP-2 dose-dependently decreased by 55% and 75% on 72 h by treatment with 25 and 50 microM delta-tocotrienol, respectively. From these findings, delta-tocotrienol at up to 50 microM dose-dependently caused a reduction in melanin content by the decrease of TRP-1 and TRP-2 as well as tyrosinase, and no cytotoxicity.
Gamma-Tocotrienol reduces squalene hydroperoxide-induced inflammatory responses in HaCaT keratinocytes
Nakagawa K, Shibata A, Maruko T, Sookwong P, Tsuduki T, Kawakami K, Nishida H, Miyazawa T.
Lipids. 2010 Sep;45(9):833-41.
Squalene hydroperoxide (SQ-OOH), the primary peroxidation product of squalene (SQ), accumulates at the surface of sunlight-exposed human skin. There are however only a few studies on the pathogenic actions (i.e., inflammatory stimuli) of SQ-OOH. Here, we evaluated whether SQ-OOH induced inflammatory responses in immortalized human keratinocytes (HaCaT). We found that SQ-OOH caused an increase in the expression of inflammatory genes such as the interleukins as well as cyclooxygenase-2 (COX-2). In concordance with the upregulation of COX-2 mRNA, SQ-OOH enhanced reactive oxygen species generation, nuclear factor kappa B activation, COX-2 protein expression, and prostaglandin E2 production. Therefore, the pro-inflammatory effects of SQ-OOH may be mediated in part via COX-2. On the other hand, gamma-tocotrienol (gamma-T3, an unsaturated form of vitamin E) was found to ameliorate the SQ-OOH actions. These results suggest that SQ-OOH induces inflammatory responses in HaCaT, implying that SQ-OOH plays an important role in inflammatory skin disorders. As a preventive strategy, inflammation could be reduced via the use of gamma-T3.
Vitamin E for Nonalcoholic Steatohepatitis: Ready for Prime Time?
Sanyal AJ, Chalasani N, Kowdley KV, McCullough A,Diehl AM, Bass NM, et al.
Hepatology. 2010 Aug;52(2):789-92.
Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of alpha-TOS with lower number of methyl substitutions on the aromatic ring were less active than alpha-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on alpha-TOS and delta-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of gamma-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.
The oil palm tree, Elaeis guineesis, is the source of palm oil, otherwise known as the “tropical golden oil”. To date, Malaysia and Indonesia are the leading producers of palm oil. Palm oil is widely used for domestic cooking in Malaysia. Palm oil is a rich source of phytonutrients such astocotrienols, tocopherol, carotene, phytosterols, squalene, coenzyme Q10, polyphenols, and phospholipids. Although the phytonutrients constitute only about 1% of its weight in crude palm oil, these are the main constituents through which palm oil exhibits its nutritional properties. Among the major health promoting properties shown to be associated with the various types of phytonutrients present in palm oil are anti-cancer, cardio-protection and anti-angiogenesis, cholesterol inhibition, brain development and neuro protective properties, antioxidative defence mechanisms, provitamin A activity and anti-diabetes.