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Tocotrienol and Its Role in Chronic Diseases

Chin KY, Pang KL, Soelaiman IN

Adv Exp Med Biol, 2016;928:97-130.
PMID: 27671814

Tocotrienol is a member of vitamin E family and is well-known for its antioxidant and anti-inflammatory properties. It is also a suppressor of mevalonate pathway responsible for cholesterol and prenylated protein synthesis. This review aimed to discuss the health beneficial effects of tocotrienol, specifically in preventing or treating hyperlipidaemia, diabetes mellitus, osteoporosis and cancer with respect to these properties. Evidence from in vitro, in vivo and human studies has been examined. It is revealed that tocotrienol shows promising effects in preventing or treating the health conditions previously mentioned in in vivo and in vitro models. In some cases, alpha-tocopherol attenuates the biological activity of tocotrienol. Except for its cholesterol-lowering effects, data on the health-promoting effects of tocotrienol in human are limited. As a conclusion, the encouraging results on the health beneficial effects of tocotrienol should motivate researchers to explore its potential use in human.

Matched MeSH terms: Tocotrienols/pharmacology; Tocotrienols/therapeutic use*
Tocotrienol-rich fraction supplementation prevents foetal loss in females mated with corticosterone-treated male Sprague-Dawley rats

Abd Aziz NAA, Chatterjee A, Chatterjee R, Durairajanayagam D

Andrologia, 2019 Apr;51(3):e13199.
PMID: 30461035 DOI: 10.1111/and.13199

This study examined whether tocotrienol supplementation to corticosterone-treated male rats could prevent foetal loss in females upon their mating. Epididymides of adult male Sprague-Dawley (SD) rats with proven fertility were surgically separated at the testis-caput junction. Twenty-four hours post-surgery, these animals received for 7 days either: tocopherol-stripped corn oil (Control), corticosterone 25 mg/kg s.c. (CORT), CORT 25 mg/kg s.c. and tocotrienol-rich fraction (TRF) 100 mg/kg orally (CORT + TRF) or TRF 100 mg/kg orally (TRF). On day 8, males were cohabited with proestrus females. A spermatozoa-positive vaginal smear indicated pregnancy. Males were euthanised for analysis of testosterone and antioxidant activities. Reproductive organs were weighed. On day 8 of pregnancy, females were laparotomised to count the number of implantation sites. Pregnancy was continued until term. Number of pups delivered and their weights were determined. Data were analysed using ANOVA. Malondialdehyde levels were significantly lower in CORT + TRF group compared with CORT group. Enzymatic antioxidant activities, testosterone level and reproductive organ weights were significantly higher in CORT + TRF group compared with CORT group. Number of implantation sites and live pups delivered, and their birth weights from females mated with CORT + TRF males were significantly higher compared to CORT group. Therefore, TRF prevents foetal loss in females mated with CORT + TRF-treated males.

Matched MeSH terms: Tocotrienols/administration & dosage; Tocotrienols/therapeutic use*
Tocotrienols: inflammation and cancer

Nesaretnam K, Meganathan P

Ann N Y Acad Sci, 2011 Jul;1229:18-22.
PMID: 21793834 DOI: 10.1111/j.1749-6632.2011.06088.x

Inflammation is an organism's response to environmental assaults. It can be classified as acute inflammation that leads to therapeutic recovery or chronic inflammation, which may lead to the development of cancer and other ailments. Genetic changes that occur within cancer cells themselves are responsible for many aspects of cancer development but are dependent on ancillary processes for tumor promotion and progression. Inflammation has long been associated with the development of cancer. The distinct characteristics of cancer cells to proliferate, metastasize, evade apoptotic signals, and develop chemoresistance have been linked to the inflammatory response. Due to the involvement of multiple genes and various pathways, current drugs that target single genes have not been effective in providing a therapeutic cure. On the other hand, natural products target multiple genes and therefore have better success compared to drugs. Tocotrienols, the potent isoforms of vitamin E, are such a natural product. This review will discuss the relationship between cancer and inflammation with particular focus on the roles played by NF-κB, STAT3, and COX-2.

Matched MeSH terms: Tocotrienols/pharmacology*
Tocotrienol-rich fraction from palm oil and gene expression in human breast cancer cells

Nesaretnam K, Ambra R, Selvaduray KR, Radhakrishnan A, Canali R, Virgili F

Ann N Y Acad Sci, 2004 Dec;1031:143-57.
PMID: 15753141

Vitamin E is important not only for its cellular antioxidant and lipid-lowering properties, but also as an antiproliferating agent. It has also been shown to contribute to immunoregulation, antibody production, and resistance to implanted tumors. It has recently been shown that tocotrienols are the components of vitamin E responsible for growth inhibition in human breast cancer cells in vitro as well as in vivo through estrogen-independent mechanisms. Although tocotrienols act on cell proliferation in a dose-dependent manner and can induce programmed cell death, no specific gene regulation has yet been identified. In order to investigate the molecular basis of the effect of a tocotrienol-rich fraction (TRF) from palm oil, we performed a cDNA array analysis of cancer-related gene expression in estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cells. The human breast cancer cells were incubated with or without 8 mug/mL of tocotrienols for 72 h. RNA was subsequently extracted and subjected to reverse transcription before being hybridized onto cancer arrays. Tocotrienol supplementation modulated significantly 46 out of 1200 genes in MDA-MB-231 cells. In MCF-7 cells, tocotrienol administration was associated with a lower number of affected genes. Interestingly, only three were affected in a similar fashion in both cell lines: c-myc binding protein MM-1, 23-kDa highly basic protein, and interferon-inducible protein 9-27 (IFITM-1). These proteins are most likely involved in the cell cycle and can exert inhibitory effects on cell growth and differentiation of the tumor cell lines. These data suggest that tocotrienols are able to affect cell homeostasis, possibly independent of their antioxidant activity.

Matched MeSH terms: Tocotrienols/analysis; Tocotrienols/pharmacology*
Tocotrienols for bone health: a translational approach

Shen CL, Klein A, Chin KY, Mo H, Tsai P, Yang RS, et al.

Ann N Y Acad Sci, 2017 Aug;1401(1):150-165.
PMID: 28891093 DOI: 10.1111/nyas.13449

Osteoporosis, a degenerative bone disease, is characterized by low bone mass and microstructural deterioration of bone tissue resulting in aggravated bone fragility and susceptibility to fractures. The trend of extended life expectancy is accompanied by a rise in the prevalence of osteoporosis and concomitant complications in the elderly population. Epidemiological evidence has shown an association between vitamin E consumption and the prevention of age-related bone loss in elderly women and men. Animal studies show that ingestion of vitamin E, especially tocotrienols, may benefit bone health in terms of maintaining higher bone mineral density and improving bone microstructure and quality. The beneficial effects of tocotrienols on bone health appear to be mediated via antioxidant/anti-inflammatory pathways and/or 3-hydroxy-3-methylglutaryl coenzyme A mechanisms. We discuss (1) an overview of the prevalence and etiology of osteoporosis, (2) types of vitamin E (tocopherols versus tocotrienols), (3) findings of tocotrienols and bone health from published in vitro and animal studies, (4) possible mechanisms involved in bone protection, and (5) challenges and future direction for research.

Matched MeSH terms: Tocotrienols/pharmacology; Tocotrienols/therapeutic use*
6th COSTAM/SFRR (ASEAN/Malaysia) International Workshop on Micronutrients, Oxidative Stress, and the Environment

Nesaretnam K, Sies H

Antioxid Redox Signal, 2006 10 13;8(11-12):2175-7.
PMID: 17034360

The 6(th) COSTAM/SFRR (ASEAN/Malaysia) workshop, "Micronutrients, Oxidative Stress, and the Environment," was held from June 29 to July 2 at Holiday Inn Damai Beach Resort in Kuching, Sarawak. Two hundred twenty participants from 17 countries presented recent advances on natural antioxidants in the area of oxidative stress and molecular aspects of nutrition. Natural products and research are an important program in academic institutions and are experiencing unprecedented interest and growth by the scientific community and public health authorities. Progress is being driven by better understanding of the molecular mechanisms of the relation between oxidative stress and micronutrient action. The gathering of scientists from around the world was fruitful, and we hope that future work will be developed by the formal and informal interactions that took place in this beautiful tropical setting.

Matched MeSH terms: Tocotrienols/pharmacology; Tocotrienols/therapeutic use
Fulltext Modulation of Ki67 and myogenic regulatory factor expression by tocotrienol-rich fraction ameliorates myogenic program of senescent human myoblasts

Tan CM, Najib NAM, Suhaimi NF, Halid NA, Cho VV, Abdullah SI, et al.

Arch Med Sci, 2021;17(3):752-763.
PMID: 34025846 DOI: 10.5114/aoms.2019.85449

Introduction: Replicative senescence results in dysregulation of cell proliferation and differentiation, which plays a role in the regenerative defects observed during age-related muscle atrophy. Vitamin E is a well-known antioxidant, which potentially ameliorates a wide range of age-related manifestations. The aim of this study was to determine the effects of tocotrienol-rich fraction (TRF) in modulating the expression of proliferation- and differentiation-associated proteins in senescent human myoblasts during the differentiation phase.
Material and methods: Human skeletal muscle myoblasts were cultured until senescence. Young and senescent cells were treated with TRF for 24 h before and after differentiation induction, followed by evaluation of cellular morphology and efficiency of differentiation. Expression of cell proliferation marker Ki67 protein and myogenic regulatory factors MyoD and myogenin were determined.
Results: Our findings showed that treatment with TRF significantly improved the morphology of senescent myoblasts. Promotion of differentiation was observed in young and senescent myoblasts with TRF treatment as shown by the increased fusion index and larger size of myotubes. Increased Ki67 and myogenin expression with TRF treatment was also observed in senescent myoblasts, suggesting amelioration of the myogenic program by TRF during replicative senescence.
Conclusions: TRF modulates the expression of regulatory factors related to proliferation and differentiation in senescent human myoblasts and could be beneficial for ameliorating the regenerative defects during aging.

Matched MeSH terms: Tocotrienols
Arterial compliance and vitamin E blood levels with a self emulsifying preparation of tocotrienol rich vitamin E

Rasool AH, Rahman AR, Yuen KH, Wong AR

Arch Pharm Res, 2008 Sep;31(9):1212-7.
PMID: 18806966 DOI: 10.1007/s12272-001-1291-5

The tocotrienol vitamin E has potent antioxidant property, however absorption is low due to high lipid solubility. A self emulsifying preparation of tocotrienol rich vitamin E (SF-TRE) had been reported to increase their bioavailability. This randomized, placebo controlled, blinded end point clinical study aimed to determine the effects of 50, 100 and 200 mg daily of SF-TRE and placebo for two months on arterial compliance and vitamin E blood levels. Assessment of arterial compliance by carotid femoral pulse wave velocity (PWV) and augmentation index (AI), plasma vitamin E, serum total cholesterol and low density lipoprotein cholesterol were taken before and after 2 months' treatment in 36 healthy males. Un-supplemented tocotrienol levels were low, after treatment, all SF-TRE treated groups had significantly higher plasma alpha, delta and delta tocotrienol concentrations compared to placebo. Augmentation index change from baseline to end of treatment for groups placebo, 50, 100, and 200 mg were 2.22+/-1.54, -6.59+/-2.84, -8.72+/-3.77, and -6.27+/-2.67% respectively (p=0.049, 0.049, and 0.047 respectively). Groups 100 and 200 mg showed significant improvement after treatment with pulse wave velocity reductions of 0.77 m/s and 0.65 m/s respectively (p=0.007 and p=0.002). There was no effect of SF-TRE on serum lipids. We conclude that there was a trend towards improvement in arterial compliance with 2 months' of SF-TRE.

Matched MeSH terms: Tocotrienols/administration & dosage*; Tocotrienols/blood*; Tocotrienols/pharmacokinetics
Effects of tocotrienols on cell viability and apoptosis in normal murine liver cells (BNL CL.2) and liver cancer cells (BNL 1ME A.7R.1), in vitro

Har CH, Keong CK

Asia Pac J Clin Nutr, 2005;14(4):374-80.
PMID: 16326644

The effects of tocotrienols on murine liver cell viability and their apoptotic events were studied over a dose range of 0-32 microg mL(-1). Normal murine liver cells (BNL CL.2) and murine liver cancer cells (BNL 1ME A.7R.1) were treated with tocotrienols (T(3)), alpha tocopherol (alpha-T) and the chemo drug, Doxorubicin (Doxo, as a positive control). Cell viability assay showed that T(3) significantly (P < or = 0.05) lowered the percentage of BNL 1ME A.7R.1 cell viability in a dose-responsive manner (8-16 microg mL(-1)), whereas T did not show any significant (P>0.05) inhibition in cell viability with increasing treatment doses of 0-16 microg mL(-1). The IC(50) for tocotrienols were 9.8, 8.9, 8.1, 9.7, 8.1 and 9.3 microg mL(-1) at 12, 24, 36, 48, 60 and 72 hours respectively. Early apoptosis was detected 6 hours following T(3) treatment of BNL 1ME A.7R.1 liver cancer cells, using Annexin V-FITC fluorescence microscopy assay for apoptosis, but none were observed for the non-treated liver cancer cells at the average IC(50) of 8.98 microg mL(-1) tocotrienols for liver cancer cells. Several apoptotic bodies were detected in BNL 1ME A.7R.1 liver cancer cells at 6 hours post-treatment with tocotrienols (8.98 microg mL(-1)) using Acridine Orange/Propidium Iodide fluorescence assay. However, only a couple of apoptotic bodies were seen in the non-treated liver cancer cells and the BNL CL.2 normal liver cells. Some mitotic bodies were also observed in the T(3)-treated BNL 1ME A.7R.1 liver cancer cells but were not seen in the untreated BNL 1ME A.7R.1 cells and the BNL CL.2 liver cells. Following T(3)-treatment (8.98 microg mL(-1)) of the BNL 1ME A.7R.1 liver cancer cells, 24.62%, 25.53% and 44.90% of the cells showed elevated active caspase 3 activity at 9, 12 and 24 hours treatment period, respectively. DNA laddering studies indicated DNA fragmentation occurred in the T(3)-treated liver cancer cells, BNL 1ME A.7R.1 but not in non-treated liver cancer cells and the T(3)-treated and non-treated normal liver cells. These results suggest that tocotrienols were able to reduce the cell viability in the murine liver cancer cells at a dose of 8-32 microg mL(-1) and that this decrease in percentage cell viability may be due to apoptosis.

Matched MeSH terms: Tocotrienols/pharmacology*
Fulltext A comparison between tocopherol and tocotrienol effects on gastric parameters in rats exposed to stress

Azlina MF, Nafeeza MI, Khalid BA

Asia Pac J Clin Nutr, 2005;14(4):358-65.
PMID: 16326642

Rats exposed to stress developed various changes in the gastrointestinal tract and hormones. The present study was designed to compare the impact of tocopherol and tocotrienol on changes that influence gastric and hormonal parameters important in maintaining gastric mucosal integrity in rats exposed to restrain stress. These include gastric acidity, gastric tissue content of parameters such as malondialdehyde, prostaglandin (PGE(2)), serum levels of gastrin and glucagon-like peptide-1 (GLP-1). Sixty male Sprague-Dawley rats (200-250 g) were randomly divided into three equal sized groups, a control group which received a normal rat diet (RC) and two treatment groups each receiving a vitamin deficient diet with oral supplementation of either tocopherol (TF) or tocotrienol (TT) at 60 mg/kg body weight. Blood samples were taken from half the number of rats (non-stressed group) after a treatment period of 28 days before they were killed. The remaining half was subjected to experimental restraint-stress, at 2 hours daily for 4 consecutive days (stressed groups), on the fourth day, blood samples were taken and the rats killed. The findings showed that the gastric acid concentration and serum gastrin level in stressed rats were significantly (P<0.05) reduced compared to the non-stressed rats in the control and TF groups. However, the gastric acidity and gastrin levels in the TT group were comparable in stressed and non-stressed rats. These findings suggest that tocotrienol is able to preserve the gastric acidity and serum gastrin level which are usually altered in stressed conditions. The PGE(2) content and the plasma GLP-1 level were, however, comparable in all stressed and non-stressed groups indicating that these parameters were not altered in stress and that supplementation with TF or TT had no effect on the gastric PGE2 content or the GLP-1 level. The malondialdehyde, an indicator of lipid peroxidation was higher from gastric tissues in the stressed groups compared to the non-stressed groups. These findings implicated that free radicals may play a role in the development of gastric injury in stress and supplementation with either TF or TT was able to reduce the lipid peroxidation levels compared to the control rats. We conclude that both tocopherol and tocotrienol are comparable in their gastro-protective ability against damage by free radicals generated in stress conditions, but only tocotrienol has the ability to block the stress-induced changes in the gastric acidity and gastrin level.

Matched MeSH terms: Tocotrienols/pharmacology*
Tocotrienols are needed for normal bone calcification in growing female rats

Norazlina M, Ima-Nirwana S, Abul Gapor MT, Abdul Kadir Khalid B

Asia Pac J Clin Nutr, 2002;11(3):194-9.
PMID: 12230232

In this study the effects of vitamin E deficiency and supplementation on bone calcification were determined using 4-month-old female Sprague-Dawley rats. The rats weighed between 180 and 200 g. The study was divided in three parts. In experiment I the rats were given normal rat chow (RC, control group), a vitamin E deficient (VED) diet or a 50% vitamin E deficient (50%VED) diet. In experiment 2 the rats were given VED supplemented with 30 mg/kg palm vitamin E (PVE30), 60 mg/kg palm vitamin E (PVE60) or 30 mg/kg pure alpha-tocopherol (ATF). In experiment 3 the rats were fed RC and given the same supplements as in experiment 2. The treatment lasted 8 months. Vitamin E derived from palm oil contained a mixture of ATF and tocotrienols. Rats on the VED and 50%VED diets had lower bone calcium content in the left femur compared to the RC group (91.6 +/- 13.3 mg and 118.3 +/- 26.0 mg cf 165.7 +/- 15.2 mg; P < 0.05) and L5 vertebra (28.3 +/- 4.0 mg and 39.5 +/- 6.2 mg compared with 51.4 +/- 5.8 mg; P < 0.05). Supplementing the VED group with PVE60 improved bone calcification in the left femur (133.6 +/- 5.0 mg compared with 91.6 +/- 13.3 mg; P < 0.05) and L5 vertebra (41.3 +/- 3.3 mg compared with 28.3 +/- 4.0 mg; P < 0.05) while supplementation with PVE30 improved bone calcium content in the L5 vertebra (35.6 +/- 3.1 mg compared with 28.3 +/- 4.0 mg; P < 0.05). However, supplementation with ATF did not change the lumbar and femoral bone calcium content compared to the VED group. Supplementing the RC group with PVE30, PVE60 or ATF did not cause any significant changes in bone calcium content. In conclusion, vitamin E deficiency impaired bone calcification. Supplementation with the higher dose of palm vitamin E improved bone calcium content, but supplementation with pure ATF alone did not. This effect may be attributed to the tocotrienol content of palm vitamin E. Therefore, tocotrienols play an important role in bone calcification.

Matched MeSH terms: Tocotrienols/administration & dosage; Tocotrienols/metabolism*
Fulltext Comparative effects of a tocotrienol-rich fraction and tocopherol in aspirin-induced gastric lesions in rats

Nafeeza MI, Fauzee AM, Kamsiah J, Gapor MT

Asia Pac J Clin Nutr, 2002;11(4):309-13.
PMID: 12495264

This study examined the effects of a tocotrienol-rich fraction (TRF) obtained from palm oil on the healing of aspirin-induced gastric mucosal lesions. Thirty-six male Sprague-Dawley rats (200-250 g) were randomly divided into three groups. Group I was fed a vitamin E-deficient diet (control), Group II was fed a vitamin E-deficient diet supplemented with tocopherol (300 mg/kg food) and Group III was fed a vitamin E-deficient diet supplemented with TRF (300 mg/kg food). After eight weeks, the control and treated groups received a single intragastric dose of 400 mg/kg body weight aspirin. The rats were killed 24 h after exposure to aspirin. Assessment of gastric lesions showed a lower gastric lesion index in the TRF (P = 0.0005) and tocopherol groups (P = 0.0008) compared to the control. The gastric malondialdehyde (MDA) content was also lower in the TRF (P = 0.025) and tocopherol groups (P = 0.025) compared to control. There were, however, no significant differences in the gastric lesion index and gastric MDA content between the TRF and tocopherol-fed groups. There were no significant differences in the adherent gastric mucous concentration and gastric acid concentration among all groups. We conclude that the TRF and tocopherol are equally effective in preventing aspirin-induced gastric lesions. The most probable mechanism is through their ability to limit lipid peroxidation, which is involved in aspirin-induced gastric lesions.

Matched MeSH terms: Tocotrienols/administration & dosage*; Tocotrienols/pharmacology
Palm vitamin E and the healing of ethanol-induced gastric lesions

Ismail NM, Jaarin K, Ahmad A, Marzuki A, Ng WK, Gapor MT

Asia Pac J Clin Nutr, 1999 Dec;8(4):258-62.
PMID: 24394225

The main focus of the study was to examine the effect of palm vitamin E (a tocotrienol-enriched fraction of palm oil) on the healing of ethanol-induced gastric mucosal lesions. The study was divided into three sections.Study 1 determined the gastric content of vitamin E after dietary supplementation with palm vitamin E for 3 weeks. Seven rats were fed a normal diet and another 7 were fed a palm vitamin E-enriched diet (150 mg/kg food). The gastric content of vitamin E levels were higher in rats fed with a palm vitamin E-enriched diet (p<0.01). Study 2 determined the time-dependent effects of palm vitamin E on gastric lesions and gastric acidity postethanol administration. Two groups of rats were fed either a normal rat diet or a palm vitamin E-enriched diet (150 mg/kg food). After 3 weeks, the control and a treated group received a single intragastric dose of 100% ethanol. Assessment of gastric lesions after 1 week showed a lower gastric lesion index in the palm vitamin E group compared with the controls (p<0.05) but there was no difference in the gastric acid content after 1 week between the two groups. Study 3 determined the effects of palm vitamin E on the gastric tissue content of malondialdehyde (MDA), PGE2 and gastric acidity without ethanol administration. The MDA content was lower in the palm vitamin E-treated group (p<0.05). However, the gastric acid and PGE2 content in both groups did not differ. The findings suggest that feeding with a palm vitamin E-enriched diet (150 mg/kg food) for 3 weeks resulted in a significant concentration of vitamin E in the gastric tissue. It was concluded that palm vitamin E may promote the healing of ethanol-induced gastric lesions through minimizing the lipid preoccupation process in the gastric mucous.

Matched MeSH terms: Tocotrienols
Long-term tocotrienol supplementation and glutathione-dependent enzymes during hepatocarcinogenesis in the rat

Rahmat A, Wan Ngah WZ, Gapor A, Khalid BA

Asia Pac J Clin Nutr, 1993 Sep;2(3):129-34.
PMID: 24352144

The effects of long-term administration of tocotrienol on hepatocarcinogenesis in rats induced by diethyl nitrosamine (DEN) and 2-acetylaminofluorene (AAF) were investigated by the determination of plasma and liver gamma-glutamyl transpeptidase (GGT), cytosolic glutathione reductase (GSSG-Rx), glutathione peroxidase (GSH-Px) and glutathione S-transferase (GST). Twenty-eight male Rattus norwegicus rats (120-160g) were divided according to treatments into four groups: control group, tocotrienol - supplemented diet group (30mg/kg food), DEN/AAF-treated group and DEN/AAF treated plus tocotrienol-supplemented-diet group (30mg/kg food). The rats were sacrificed after nine months. The results obtained indicated no difference in the morphology and histology of the livers of control and tocotrienol-treated rats. Greyish-white neoplastic nodules (two per liver) were found in all the DEN/ AAF treated rats (n-10) whereas only one nodule was found in one of the carcinogen treated rats receiving tocotrienol supplementation (n-6). Histological examination showed obvious cellular damage for both the DEN/AAF-treated rats and the tocotrienol-supplemented rats but were less severe in the latter. Treatment with DEN/AAF caused increases in GGT, GSH-Px, GST and GSSG-Rx activities when compared to controls. These increases were also observed when tocotrienol was supplemented with DEN/AAF but the increases were less when compared to the rats receiving DEN/AAF only.

Matched MeSH terms: Tocotrienols
Palm oil tocotrienols and plant flavonoids act synergistically with each other and with Tamoxifen in inhibiting proliferation and growth of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 human breast cancer cells in culture

Guthrie N, Gapor A, Chambers AF, Carroll KK

Asia Pac J Clin Nutr, 1997 Mar;6(1):41-5.
PMID: 24394652

Palm oil, unlike many other dietary oils, does not increase the yield of chemically-induced mammary tumors in rats when fed at high levels in the diet. This difference appears to be due to the vitamin E fraction of palm oil, which is rich in tocotrienols, since palm oil stripped of this fraction does increase tumor yields. Experiments in our laboratory have shown that tocotrienols inhibit proliferation and growth of both MDA-MB-435 and MCF-7 cells in culture much more effectively than a-tocopherol. In addition, it was found that combinations of tocotrienols with Tamoxifen, a drug widely used for treatment of breast cancer, inhibit these cells more effectively than either tocotrienols or Tamoxifen alone. The present studies have now shown synergistic effects between tocotrienols and a number of other flavonoids from various plant sources, including citrus fruits, in the inhibition of both MDA-MB-435 and MCF-7 cells (IC50s 0.05-25 and 0.02-5 μg/mL respectively). In the MCF-7 cells, 1:1:1 combinations of tocotrienols, flavonoids and Tamoxifen were even more effective, with the best combination being d-tocotrienol, hesperetin and Tamoxifen (IC50 0.0005 μg/mL). These results suggest that diets containing palm oil may reduce the risk of breast cancer, particularly when eaten with other plant foods containing flavonoids, and may also enhance the effectiveness of Tamoxifen for treatment of breast cancer.

Matched MeSH terms: Tocotrienols
Modulation of human lipids and lipoproteins by dietary palm oil and palm olein: a review

Sundram K

Asia Pac J Clin Nutr, 1997 Mar;6(1):12-6.
PMID: 24394646

Several human clinical trials have now evaluated palm oil's effects on blood lipids and lipoproteins. These studies suggest that palm oil and palm olein diets do not raise plasma TC and LDL-cholesterol levels to the extent expected from its fatty acid composition. With maximum substitution of palm oil in a Western type diet some coronary heart disease risk factors were beneficially modulated: HDL2-cholesterol was significantly increased while the apolipoprotein B/A1 ratio was beneficially lowered by palm oil. Comparison of palm olein with a variety of monounsaturated edible oils including rapeseed, canola, and olive oils has shown that plasma and LDL-cholesterol were not elevated by palm olein. To focus these findings, specific fatty acid effects have been evaluated. Myristic acid may be the most potent cholesterol raising saturated fatty acid. Palmitic acid effects were largely comparable to the monounsaturated oleic acid in normolipidaemic subjects while trans fatty acids detrimentally increased plasma cholesterol, LDL-cholesterol, lipoprotein Lp(a) and lowered the beneficial HDL-cholesterol. Apart from these fatty acids there is evidence that the tocotrienols in palm oil products may have a hypocholesterolaemic effect. This is mediated by the ability of the tocotrienols to suppress HMG-CoA reductase. These new findings on palm oil merit a scientific reexamination of the classical saturated fat-lipid hypothesis and its role in lipoprotein regulation.

Matched MeSH terms: Tocotrienols
Lipidaemic effects of tocotrienols, tocopherols and squalene: studies in the hamster

Khor HT, Chieng DY

Asia Pac J Clin Nutr, 1997 Mar;6(1):36-40.
PMID: 24394651

Syrian Golden hamsters have been widely used as a experimental model for the investigation of the aetiology and development of atherosclerosis and cardiovascular disease. The responses of the hamster to dietary fat manipulations are in many ways similar to that observed in humans. The lipidaemic effect of a tocotrienol rich fraction (TRF) from palm oil on human trials has not been consistent. In this study, the cholesterolaemic effect of tocotrienols and tocopherols were differentiated by using pure tocotrienols (that were isolated from palm oil fatty acid distillate) and pure commercial tocopherols and squalene. A palm oil triacylglycerol fraction (POTG), free of all unsaponifiable matter, was used as the dietary fat in different feeding experiments. Tocotrienols added at 162 ppm to POTG (POTG-T3L) significantly (p<0.05) lowered serum total cholesterol (TC) level as compared to that of the POTG group; but the serum LDL-C , HDL-C and TG levels of the POTG-T3L group were not significantly lower than that of the POTG group (P>0.05). Increasing the level of tocotrienol supplementation to the diet (POTG-T3H) appeared to raise rather then reduce the serum TC, LDL-C and HDL-C levels as compared to that of POTG-T3L group. This observation that lower level of tocotrienol supplementation appeared to exhibit stronger hypocholesterolaemic effect than a higher level of tocotrienol supplementation is interesting; but its explanation is not yet forthcoming. When tocopherols were supplemented at 72 ppm to the POTG diet it was observed that the serum TC, LDL-C and HDL-C levels were all somewhat increased when compared to that of the POTG group. These results suggest that tocotrienols and tocopherols may have opposite cholesterolaemic effects in the hamster, and further experiments need to clarify the mode of action of these vitamin E isomers. In our second series of experiments the cholesterolaemic effects of tocotrienols and tocopherols were studied in the presence of squalene, a key intermediate in the cholesterol synthesis pathway and a controversial cholesterol lowering agent. Squalene added to the diet at 0.1% level significantly lowered (p<0.05) serum TC level when compared to that of the POTG group. The LDL-C, HDL-C and TG levels appeared to be lowered by the squalene supplementation also but the differences between the POTG-SQ and POTG groups were not statistically significant (P>0.05). When tocotrienols or tocopherols were added to the squalene-containing POTG diets, the serum TC and LDL-C levels were further reduced (p<0.01) when compared to that of the POTG and POTG-SQ groups. The HDL-C and TG levels were not affected by tocotrienol or tocopherol supplementation in the presence of squalene. These results indicate that in the presence of tocotrienols and squalene POTG exhibit hypocholesterolaemic action whereas tocopherols may have a hypercholesterolaemic effect in the hamster.

Matched MeSH terms: Tocotrienols
Fulltext Tocotrienol levels in adipose tissue of benign and malignant breast lumps in patients in Malaysia

Nesaretnam K, Gomez PA, Selvaduray KR, Razak GA

Asia Pac J Clin Nutr, 2007;16(3):498-504.
PMID: 17704032

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.

Matched MeSH terms: Tocotrienols/analysis*
Fulltext Tocotrienols are good adjuvants for developing cancer vaccines

Hafid SR, Radhakrishnan AK, Nesaretnam K

BMC Cancer, 2010;10:5.
PMID: 20051142 DOI: 10.1186/1471-2407-10-5

Dendritic cells (DCs) have the potential for cancer immunotherapy due to their ability to process and present antigens to T-cells and also in stimulating immune responses. However, DC-based vaccines have only exhibited minimal effectiveness against established tumours in mice and humans. The use of appropriate adjuvant enhances the efficacy of DC based cancer vaccines in treating tumours.

Matched MeSH terms: Tocotrienols/pharmacology*
Fulltext Cytotoxicity and apoptotic activities of alpha-, gamma- and delta-tocotrienol isomers on human cancer cells

Lim SW, Loh HS, Ting KN, Bradshaw TD, Zeenathul NA

BMC Complement Altern Med, 2014;14:469.
PMID: 25480449 DOI: 10.1186/1472-6882-14-469

Tocotrienols, especially the gamma isomer was discovered to possess cytotoxic effects associated with the induction of apoptosis in numerous cancers. Individual tocotrienol isomers are believed to induce dissimilar apoptotic mechanisms in different cancer types. This study was aimed to compare the cytotoxic potency of alpha-, gamma- and delta-tocotrienols, and to explore their resultant apoptotic mechanisms in human lung adenocarcinoma A549 and glioblastoma U87MG cells which are scarcely researched.

Matched MeSH terms: Tocotrienols/pharmacology; Tocotrienols/therapeutic use*

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