Vitamin E comprises 8 functionally unique isoforms and may be a suitable candidate for the adjuvant treatment of prostate cancer. In this study, we examined the ability of 2 vitamin E isoforms [α-tocotrienol (γ-TT) and δ-tocotrienol (δ-TT)] and 4 synthetic derivatives [γ- and δ-tocotrienol succinate (γ-TS, δ-TS), α-tocopheryl polyethylene glycol succinate (TPGS), and α-tocopheryl polyethylene glycol ether (TPGS-e)] of vitamin E to induce cell death in AR- (DU145 and PC-3) and AR+ (LNCaP) prostate cancer cell lines. Our results show that δ-TT and TPGS-e are the most effective isoform and synthetic derivative, respectively, of all compounds examined. Overall, the results of our study suggest that isoforms and synthetic derivatives of vitamin E have the potency to trigger both caspase-dependent and -independent DNA damage and dominant caspase-independent programmed cell death. The capacity of vitamin E to trigger caspase-independent programmed cell death suggests that it may be useful in the chemotherapy of prostate cancer since it may prevent the tumor resistance commonly associated with the use of classical chemotherapeutic agents that trigger caspase-dependent programmed cell death.
Publications
Neuroprotective effect of vitamin E isoforms against chronic alcohol-induced peripheral neurotoxicity: Possible involvement of oxidative-nitrodative stress
Tiwari V, Kuhad A, Chopra K.
Phytother Res. 2012 Nov;26(11):1738-45. Epub 2012 Mar 15.
Small-fiber painful peripheral neuropathy is one of the long-term complications of alcohol for which there is no reliable successful therapy available. The precise mechanisms by which chronic alcohol consumption produces peripheral nerve fiber damage and loss remain unclear. Emerging data from clinical and preclinical studies suggest that increased oxidative-nitrodative stress mediated release of proinflammatory cytokines from damaged neural tissues may play a central role in the pathogenesis of alcoholic neuropathy. The present study investigated the effect of both the isoforms of vitamin E (α-tocopherol and tocotrienol) against chronic alcohol-induced peripheral neuropathy in rats. Ethanol treated rats showed a significant decrease in paw-withdrawal threshold in both Randall-Selitto and von-Frey hair tests along with a significant reduction in tail flick latency in the tail-immersion test. A decreased pain threshold was associated with significant alterations in oxidative-nitrodative stress markers and an increase in proinflammatory cytokines (TNF-α and IL-1β). The 4-week treatment with tocotrienol significantly ameliorated behavioral, biochemical and molecular alterations in alcohol treated rats. However, α-tocopherol failed to produce any protective effect. The results of the present study suggest that oxidative-nitrodative stress mediated cytokine signaling may be responsible for alcohol-induced peripheral neurotoxicity and tocotrienol treatment might be beneficial in chronic alcoholics exhibiting neuropathy
Mechanisms mediating the synergistic anticancer effects of combined γ-tocotrienol and sesamin treatment
Akl MR, Ayoub NM, Sylvester PW.
Planta Med. 2012 Nov;78(16):1731-9.
Epidemiological studies have highlighted the ability of phytochemicals to reduce the risk of breast cancer by attenuating specific intracellular signaling pathways that regulate cell proliferation and survival. γ-Tocotrienol is a natural form of vitamin E that displays potent anticancer activity at doses that have no discernible toxicity toward normal cells. Sesamin is an abundant phytochemical found in sesame seed oil that also shows antiproliferative and antiangiogenic activity against human breast cancer cells. In this study, the combined treatment of subeffective doses of γ-tocotrienol and sesamin caused a synergistic inhibition of murine +SA mammary epithelial cell growth, as determined by the MTT assay and immunofluorescent Ki-67 staining. Western blot studies revealed that combined low-dose treatment of γ-tocotrienol and sesamin caused a marked reduction in EGF-induced ErbB3 and ErbB4 receptors phosphorylation (activation) and a relatively large decrease in intracellular levels of total and/or phosphorylated c-Raf, MEK1/2, ERK1/2, PI3K, PDK1, Akt, p-NFκB, Jak1, Jak2, and Stat1, as compared to cells treated with only one compound or in the vehicle-treated control group. These findings demonstrate that the synergistic growth inhibitory effects of γ-tocotrienol and sesamin treatment are associated with suppression of EGF-dependent mitogenic signaling in mammary tumor cells and suggest that dietary supplementation with these phytochemicals may provide some benefits in the prevention and/or treatment of breast cancer.
Inhibition of Mitochondrial Cytochrome C Release and Suppression of Caspases by Gamma-Tocotrienol Prevent Apoptosis and Delay Aging in Stress-Induced Premature Senescence of Skin Fibroblasts
Makpol S, Abdul Rahim N, Kien Hui C, Wan Ngah WZ.
Oxid Med Cell Longev. 2012;2012:785743
In this study, we determined the molecular mechanism of γ-tocotrienol (GTT) in preventing cellular aging by focusing on its anti-apoptotic effect in stress-induced premature senescence (SIPS) model of human diploid fibroblasts (HDFs). Results obtained showed that SIPS exhibited senescent-phenotypic characteristic, increased expression of senescence-associated β-galactosidase (SA β-gal) and promoted G(0)/G(1) cell cycle arrest accompanied by shortening of telomere length with decreased telomerase activity. Both SIPS and senescent HDFs shared similar apoptotic changes such as increased Annexin V-FITC positive cells, increased cytochrome c release and increased activation of caspase-9 and caspase-3 (P < 0.05). GTT treatment resulted in a significant reduction of Annexin V-FITC positive cells, inhibited cytochrome c release and decreased activation of caspase-9 and caspase-3 (P < 0.05). Gene expression analysis showed that GTT treatment down regulated BAX mRNA, up-regulated BCL2A1 mRNA and decreased the ratio of Bax/Bcl-2 protein expression (P < 0.05) in SIPS. These findings suggested that GTT inhibits apoptosis by modulating the upstream apoptosis cascade, causing the inhibition of cytochrome c release from the mitochondria with concomitant suppression of caspase-9 and caspase-3 activation. In conclusion, GTT delays cellular senescence of human diploid fibroblasts through the inhibition of intrinsic mitochondria-mediated pathway which involved the regulation of pro- and anti-apoptotic genes and proteins.
Gamma-tocotrienol modulation of senescence-associated gene expression prevents cellular aging in human diploid fibroblasts
Makpol S, Zainuddin A, Chua KH, Yusof YA, Ngah WZ.
Clinics (Sao Paulo). 2012;67(2):135-43.
Objective: Human diploid fibroblasts undergo a limited number of cellular divisions in culture and progressively reach a state of irreversible growth arrest, a process termed cellular aging. The beneficial effects of vitamin E in aging have been established, but studies to determine the mechanisms of these effects are ongoing. This study determined the molecular mechanism of γ-tocotrienol, a vitamin E homolog, in the prevention of cellular aging in human diploid fibroblasts using the expression of senescence-associated genes.
Methods: Primary cultures of young, pre-senescent, and senescent fibroblast cells were incubated with γ-tocotrienol for 24 h. The expression levels of ELN, COL1A1, MMP1, CCND1, RB1, and IL6 genes were determined using the quantitative real-time polymerase chain reaction. Cell cycle profiles were determined using a FACSCalibur Flow Cytometer.
Results: The cell cycle was arrested in the G(0)/G(1) phase, and the percentage of cells in S phase decreased with senescence. CCND1, RB1, MMP1, and IL6 were upregulated in senescent fibroblasts. A similar upregulation was not observed in young cells. Incubation with γ-tocotrienol decreased CCND1 and RB1 expression in senescent fibroblasts, decreased cell populations in the G(0)/G(1) phase and increased cell populations in the G(2)/M phase. γ-Tocotrienol treatment also upregulated ELN and COL1A1 and downregulated MMP1 and IL6 expression in young and senescent fibroblasts.
Conclusion: γ-Tocotrienol prevented cellular aging in human diploid fibroblasts, which was indicated by the modulation of the cell cycle profile and senescence-associated gene expression.
Eliminating drug resistant breast cancer stem-like cells with combination of simvastatin and gamma-tocotrienol
Gopalan A, Yu W, Sanders BG, Kline K.
Cancer Lett. 2012 Oct 9. [Epub ahead of print]
Present study shows that drug resistant human breast cancer cells are enriched in cancer stem-like cells (CSCs) and express elevated levels of Stat-3 signaling mediators, which contribute to CSC enrichment. Simvastatin (SVA) and gamma-tocotrienol (γT3) eliminate enriched CSCs and suppress expression of Stat-3 signaling mediators via inhibition of the mevalonate pathway and activation of de novo ceramide synthesis pathway, respectively. Combination of SVA+γT3 at low doses enhanced these actions via inhibition of the mevalonate pathway. Data demonstrate that SVA and γT3 alone or in combination possess the ability to eliminate CSCs in drug resistant human breast cancer cells.
Involvement of de novo ceramide synthesis in gamma-tocopherol and gamma-tocotrienol-induced apoptosis in human breast cancer cells
Gopalan A, Yu W, Jiang Q, Jang Y, Sanders BG, Kline K.
Mol Nutr Food Res. 2012 Oct 15.
Scope: This study further examines mechanisms involved in the pro-apoptotic action of gamma-tocopherol (γT) and gamma-tocotrienol (γT3) in human breast cancer cell lines.
Methods And Results: γT upregulates phospho-JNK (pJNK), CCAAT/enhancer-binding protein homologous protein (CHOP), and death receptor-5 (DR5) protein expression as detected by Western blot assays. siRNA knockdown of JNK, CHOP, or DR5 shows that γT-induced apoptosis is JNK/CHOP/DR5 signaling dependent, which is similar to γT3-mediated apoptotic signaling. Furthermore, both γT and γT3 induce increased levels of cellular ceramides and dihydroceramides as determined by LC-MS/MS analyses. Inhibition of de novo ceramide synthesis using chemical inhibitors blocked the ability of γT and γT3 to induce apoptosis as detected by Annexin V-FITC/PI assay and to activate JNK/CHOP/DR5 pro-apoptotic signaling thereby demonstrating the involvement of de novo ceramide synthesis in γT- and γT3-induced apoptosis.
Conclusion: Taken together, data show that both γT and γT3 induce apoptosis via de novo ceramide synthesis dependent activation of JNK/CHOP/DR5 pro-apoptotic signaling.
Tocopherols and tocotrienols plasma levels are associated with cognitive impairment
Francesca Mangialasche, Weili Xu, Miia Kivipelto, Emanuela Costanzi, Sara Ercolani, Martina Pigliautile, Roberta Cecchetti, Mauro Baglioni, Andrew Simmons, Hilkka Soininen, Magda Tsolaki, Iwona Kloszewska, Bruno Vella, Simon Lovestone, Patrizia Mecocci,
Neurobiol Aging. 2012 Oct;33(10):2282-90.
Vitamin E includes 8 natural compounds (4 tocopherols, 4 tocotrienols) with potential neuroprotective activity. α-Tocopherol has mainly been investigated in relation to cognitive impairment. We examined the relation of all plasma vitamin E forms and markers of vitamin E damage (α-tocopherylquinone, 5-nitro-γ-tocopherol) to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Within the AddNeuroMed-Project, plasma tocopherols, tocotrienols, α-tocopherylquinone, and 5-nitro-γ-tocopherol were assessed in 168 AD cases, 166 MCI, and 187 cognitively normal (CN) people. Compared with cognitively normal subjects, AD and MCI had lower levels of total tocopherols, total tocotrienols, and total vitamin E. In multivariable-polytomous-logistic regression analysis, both MCI and AD cases had 85% lower odds to be in the highest tertile of total tocopherols and total vitamin E, and they were, respectively, 92% and 94% less likely to be in the highest tertile of total tocotrienols than the lowest tertile. Further, both disorders were associated with increased vitamin E damage. Low plasma tocopherols and tocotrienols levels are associated with increased odds of MCI and AD.
Chemopreventive properties of dietary rice bran: Current status and future prospects
Henderson AJ, Ollila CA, Kumar A, Borresen EC, Raina K, Agarwal R, Ryan EP.
Adv Nutr. 2012 Sep 1;3(5):643-53.
Emerging evidence suggests that dietary rice bran may exert beneficial effects against several types of cancer, such as breast, lung, liver, and colorectal cancer. The chemopreventive potential has been related to the bioactive phytochemicals present in the bran portion of the rice such as ferulic acid, tricin, β-sitosterol, γ-oryzanol, tocotrienols/tocopherols, and phytic acid. Studies have shown that the anticancer effects of the rice bran-derived bioactive components are mediated through their ability to induce apoptosis, inhibit cell proliferation, and alter cell cycle progression in malignant cells. Rice bran bioactive components protect against tissue damage through the scavenging of free radicals and the blocking of chronic inflammatory responses. Rice bran phytochemicals have also been shown to activate anticancer immune responses as well as affecting the colonic tumor microenvironment in favor of enhanced colorectal cancer chemoprevention. This is accomplished through the modulation of gut microflora communities and the regulation of carcinogen-metabolizing enzymes. In addition, the low cost of rice production and the accessibility of rice bran make it an appealing candidate for global dietary chemoprevention. Therefore, the establishment of dietary rice bran as a practical food-derived chemopreventive agent has the potential to have a significant impact on cancer prevention for the global population.
Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor
Kulkarni SS, Cary LH, Gambles K, Hauer-Jensen M, Kumar KS, Ghosh SP.
Int Immunopharmacol. 2012 Sep 20;14(4):495-503. 2012.09.001. [Epub ahead of print]
Gamma-tocotrienol (GT3), a promising radioprotectant, is shown to protect CD2F1 mice from radiation-induced neutropenia and thrombocytopenia when given 24h prior to total-body irradiation. GT3 also is shown to increase white blood cells (WBC) and absolute neutrophil counts (ANC) transiently in peripheral blood. We hypothesized that increases in WBC and ANC may involve stimulation of hematopoiesis possibly by cytokines and growth factors. To evaluate the effects of GT3 on hematopoietic system, we measured various cytokines, chemokines and growth factors by cytokine array and Bio-Plex assays. Both showed strong induction of various cytokines and chemokines. GT3 treatment resulted in significant increases in G-CSF, IL-1α, IL-1β, IL-6, IL-12p70, IL-17, MIP-1α, and KC levels. G-CSF levels increased markedly within 12-24h after administration (5441pg/ml in GT3-treated groups compared to 17pg/ml in vehicle control). Most of these cytokine levels were elevated in the presence or absence of radiation. Time-course analysis of G-CSF and IL-6 induction showed that both cytokines were induced transiently after GT3 administration, and returned to normal levels by 48h post-administration. For G-CSF, the peak was observed between 12 and 24h post-administration of GT3; however, the highest levels of IL-6 were obtained between 6 and 12h. These results demonstrate that GT3 induced high levels of G-CSF and other inflammatory cytokines and chemokines within 24h after administration. Survival studies reported showed that the most efficacious time for administering GT3 was 24h prior to irradiation, possibly because it induced key hematopoietic cytokines in that time window. These results also suggest a possible role of GT3-induced G-CSF stimulation in protecting mice from radiation-induced neutropenia and thrombocytopenia.