Multitargeted therapy of cancer by tocotrienols

doi:10.1016/j.canlet.2008.03.063

Cancer Letters

Volume 269, Issue 2, 8 October 2008, Pages 388-395

https://doi.org/10.1016/j.canlet.2008.03.063 Get rights and content

Abstract

Natural compounds with possible health benefits have become attractive targets for research in areas pertaining to human health. For both prevention and therapy of various human ailments, such compounds are preferred over synthetic ones due to their lesser toxicity. They are also easily absorbed and processed by our body. Vitamins are prominent among natural or endogenous compounds that are considered to be beneficial. The vitamin E group of compounds is among the better known of the vitamins due to their suggested health benefits including antioxidant and related protective properties. Among these, tocotrienols have gained prominence in recent years due to their potential applications and better protective effects in certain systems. These tocotrienols are vitamin E derivatives that are analogs of the more established forms of vitamin E namely tocopherols. In addition to their potent antioxidant activity, tocotrienols have other important functions, especially in maintaining a healthy cardiovascular system and a possible role in protection against cancer and other ailments.

Introduction

The edible oil industry has emerged as an important raw material for the extraction of vitamin E. Vegetable oils, especially the seed oils, are rich sources of tocopherols (Table 1). However, in palm oil, vitamin E occurs as a complex mixture of tocopherols and tocotrienols. Various tocotrienol isomers of vitamin E in palm oil have been reported to contain interesting biological and physiological properties not generally evident with tocopherol-rich vitamin E preparations. They include potential blood cholesterol lowering and cardioprotective effects, more efficient antioxidant activity in biological systems, and possible anticancer and neuroprotective effects [1]. With the emergence of palm oil as the largest edible oil in world markets, technology is now available to extract tocotrienol-rich palm vitamin E. Tocopherols (T) and tocotrienols (T3) share common structural features of a chromanol ring and a side-chain at the C-2 position [2]. The difference between tocopherols and tocotrienols is that the former contains a saturated phytyl tail, whereas the latter bears an unsaturated isoprenoid side-chain (Fig. 1). Each subgroup of vitamin E contains several isoforms. Each of these forms of vitamin E has a different biopotency [3], [4].

Section snippets

Metabolic fate of tocotrienols

Together with dietary fat, both tocopherols and tocotrienols are absorbed in the digestive tract, incorporated into chylomicrons, and transported in the lymphatic system [5]. However, following chylomicron clearance, tocotrienols disappear from circulating plasma, whereas tocopherol, especially αT, is preferentially secreted into plasma. α-Tocopherol transfer protein, which controls plasma αT levels, has an affinity of only 12% for αT3 (compared with 100% for αT). The reason for the low plasma

Antioxidant properties of tocotrienols

Vitamin E compounds are well known for their antioxidant property [2]. This property depends primarily on the phenolic group in the chromanol ring, rather than the side-chain [11]. Tocotrienols, like tocopherols are capable of scavenging and quenching free radicals. Their antioxidative activity, however, resides mainly with its chain breaking property, which neutralizes peroxyl and alkoxyl radicals generated during lipid peroxidation [2], [12]. Peroxidation of membrane lipids is known to modify

Anticancer properties of tocotrienols

During the past decade much evidence has accumulated demonstrating the anticancer activity of specific forms of vitamin E [16], [17]. Table 2 summarises some of the anticancer effects of tocotrienols. Studies have shown that individual tocopherols and tocotrienols display differential potencies in suppressing tumor cell growth and inducing apoptosis in neoplastic mammary epithelial cells that can be characterized as δ-T3 > γ-T3 > α-T3 > δ-T > γT > α-T [18], [19]. In mice, tocotrienols were compared with

Tocotrienols and breast cancer

Our early studies on breast cancer looked at the protective role palm oil played in mammary carcinogenesis, compared the positive effect conferred by palm oil, and linked it to the presence of tocotrienols [53]. Further work was then carried out in vitro and in vivo on the growth of estrogen receptor positive and receptor negative human breast cancer cells using both the TRF and the individual tocotrienols [21], [22], [23], [33]. Breast cancer was chosen as a subject for investigation as it is

Conclusion

Chemopreventive dietary strategies aimed at inhibiting tumor growth are indeed an alluring option to treat a variety of cancers. While research continues into the antioxidant actions of tocotrienol, the non-antioxidant functions of tocotrienol are beginning to steal the spotlight, particularly in the area of cancer. Tocotrienols are shown to possess the ability to combat cancer in vitro and in vivo, evidently independent of the antioxidant activity. The discovery of the antiangiogenic,

References (59)

H.J. Kayden et al.
Absorption, lipoprotein transport and regulation of plasma concentrations of vitamin E in humans
J. Lipid Res.
(1993)
E. Niki et al.
Effect of phytyl side chain of vitamin E on its antioxidant activity
J. Biol. Chem.
(1985)
J. Kamat et al.
Tocotrienols from palm oil as potent inhibitors of lipid peroxidation and protein oxidation in rat brain mitochondria
Neurosci. Lett.
(1995)
T. Eitsuka et al.
Down-regulation of telomerase activity in DLD-1 human colorectal adenocarcinoma cells by tocotrienol
BBRC
(2006)
N. Guthrie et al.
Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and positive MCF-7 human breast cancer cells by palm oil tocotrienol and tamoxifen, alone and in combination
J. Nutr.
(1997)
K. Nakagawa et al.
In vivo angiogenesis is suppressed by unsaturated vitamin E
J. Nutr.
(2007)
J.K. Srivastava et al.
Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells
Biochem. Biophys. Res. Commun.
(2006)
S. Wada et al.
Tumor suppressive effects of tocotrienol in vivo and in vitro
Cancer Lett.
(2005)
P.L. Crowell et al.
Selective inhibition of isoprenylation of 21–26-kDa proteins by the anticarcinogen d-limonene and its metabolites
J. Biol. Chem.
(1991)
C.E. Elson et al.
The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables
J. Nutr.
(1994)

R. Jesnowski et al.

Ribosomal highly basic 23-kDa protein as a reliable standard for gene expression analysis

Pancreatology

(2002)

K. Takahashi et al.

Disruption of mitochondria during tocotrienol-induced apoptosis in MDA-MB-231 human breast cancer cells

Biochem. Pharmacol.

(2004)

S. Nagata

Apoptosis by death factor

Cell

(1997)

S. Desagher et al.

Mitochondria as the central control point of apoptosis

Trends Cell Biol.

(2000)

K.S. Ahn et al.

γ-Tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein leading to suppression of antiapoptotic gene products and potentiation of apoptosis

J. Biol. Chem.

(2007)

K. Nesaretnam et al.

The Effect of Vitamin E Tocotrienols from Palm Oil on Chemically Induced Mammary Carcinogenesis in Female Rats

Nutr. Res.

(1992)

N. Boyd et al.

The possible role of lipid peroxidation in breast cancer risk

Free Radic. Biol. Med.

(1991)

A. Matsui et al.

Increased formation of oxidative DNA damage, 8-hydroxyl-2′ deoxyguanosine, in human breast cancer tissue and its relationship to GSTP1 and COMT genotypes

Cancer Lett.

(2000)

C.K. Sen et al.

Tocotrienols: vitamin E beyond tocopherols

Life Sci.

(2006)

A. Kamal-Eldin et al.

The chemistry and antioxidant properties of tocopherols and tocotrienols

Lipids

(1996)

A. Azzi et al.

Vitamin E: non-antioxidant roles

Prog. Lipid Res.

(2003)

M.G. Traber et al.

Vitamin E in humans: demand and delivery

Annu. Rev. Nutr.

(1996)

S.P. Yap et al.

Pharmacokinetics abd bioavailability of alpha, gamma, and delta-tocotrienols under different food status

J. Pharm. Pharmacol.

(2001)

R. Brigelius-Flohe et al.

Vitamin E: function and metabolism

FASEB J.

(1999)

J.K. Lodge et al.

α-and gamma-tocotrienols are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine

Lipids

(2001)

K.C. Hayes et al.

Differences in the plasma transport and tissue concentrations of tocopherols and tocotrienols: observations in humans and hamsters

Proc. Soc. Exp. Biol. Med.

(1993)

M.G. Traber et al.

Diet derived and topically applied tocotrienols accumulate in skin and protect the tissue against ultraviolet light-induced oxidative stress

Asia Pac. J. Clin. Nutr.

(1997)

G.W. Burton et al.

Vitamin E as in vitro and in vivo antioxidant

Ann. N. Y. Acad. Sci.

(1989)

K. Nesaretnam et al.

Influence of palm oil or its tocotrienol-rich fraction on lipid peroxidation potential on rat liver mitochondria and microsomes

Biochem. Mol. Biol. Int.

(1993)

Cited by (90)

Biofortification of crops with nutrients: factors affecting utilization and storage
2017, Current Opinion in Biotechnology
Citation Excerpt :
Carotenoids are lipophilic and may also compete with plant sterols and stanols for solubilization in mixed micelles [18]. Vitamin E comprises eight fat-soluble molecules (α, β, γ and δ tocopherol and the corresponding tocotrienols, with α-tocopherol possessing the greatest biological activity) and like carotenoids its bioavailability is therefore highly dependent on interactions with the food matrix [20,21]. Accordingly, the bioaccessibility of vitamin E varies extensively in different types of food, ranging from 0.47% in apple to almost 100% in banana, white bread and lettuce.
Biofortification is an effective and economical method to improve the micronutrient content of crops, particularly staples that sustain human populations in developing countries. Whereas conventional fortification requires artificial additives, biofortification involves the synthesis or accumulation of nutrients by plants at source. Little is known about the relative merits of biofortification and artificial fortification in terms of nutrient bioaccessibility and bioavailability, and much depends on the biochemical nature of the nutrient, which can promote or delay uptake, and determine how efficiently different nutrients are transported through the blood, stored, and utilized. Data from the first plants biofortified with minerals and vitamins provide evidence that the way in which nutrients are presented can affect how they are processed and utilized in the human body. The latest studies on the effects of the food matrix, processing and storage on nutrient transfer from biofortified crops are reviewed, as well as current knowledge about nutrient absorption and utilization.
Tumor regression after intravenous administration of targeted vesicles entrapping the vitamin E α-tocotrienol
2017, Journal of Controlled Release
The therapeutic potential of tocotrienol, a member of the vitamin E family of compounds with potent in vitro anti-cancer properties, is limited by its inability to specifically reach tumors following intravenous administration. The purpose of this study is to determine whether a novel tumor-targeted vesicular formulation of tocotrienol would suppress the growth of A431 epidermoid carcinoma and B16-F10 melanoma in vitro and in vivo.
In this work, we demonstrated that novel transferrin-bearing multilamellar vesicles entrapping α-T3 resulted in a dramatically improved (by at least 52-fold) therapeutic efficacy in vitro on A431 cell line, compared to the free drug. In addition, the intravenous administration of tocotrienol entrapped in transferrin-bearing vesicles resulted in tumor suppression for 30% of A431 and 60% of B16-F10 tumors, without visible toxicity. Mouse survival was enhanced by > 13 days compared to controls administered with the drug solution only.
This tumor-targeted, tocotrienol-based nanomedicine therefore significantly improved the therapeutic response in cancer treatment.
Potential of tocotrienols in the prevention and therapy of Alzheimer's disease
2016, Journal of Nutritional Biochemistry
Currently there is no cure for Alzheimer's disease (AD); clinical trials are underway to reduce amyloid generation and deposition, a neuropathological hallmark in brains of AD patients. While genetic factors and neuroinflammation contribute significantly to AD pathogenesis, whether increased cholesterol level is a causative factor or a result of AD is equivocal. Prenylation of proteins regulating neuronal functions requires mevalonate-derived farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). The observation that the levels of FPP and GGPP, but not that of cholesterol, are elevated in AD patients is consistent with the finding that statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, reduce FPP and GGPP levels and amyloid β protein production in preclinical studies. Retrospective studies show inverse correlations between incidence of AD and the intake and serum levels of the HMG CoA reductase-suppressive tocotrienols; tocopherols show mixed results. Tocotrienols, but not tocopherols, block the processing and nuclear localization of sterol regulatory element binding protein-2, the transcriptional factor for HMG CoA reductase and FPP synthase, and enhance the degradation of HMG CoA reductase. Consequently, tocotrienols deplete the pool of FPP and GGPP and potentially blunt prenylation-dependent AD pathogenesis. The antiinflammatory activity of tocotrienols further contributes to their protection against AD. The mevalonate- and inflammation-suppressive activities of tocotrienols may represent those of an estimated 23,000 mevalonate-derived plant secondary metabolites called isoprenoids, many of which are neuroprotective. Tocotrienol-containing plant foods and tocotrienol derivatives and formulations with enhanced bioavailability may offer a novel approach in AD prevention and treatment.
Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation
2023, Radiation Research
Neuroprotective effects of dietary plants and phytochemicals against radiation-induced cognitive and behavioral deficits: a comprehensive review of evidence and prospects for future research
2023, Food and Function
Preventative and therapeutic potential of tocotrienols on musculoskeletal diseases in ageing
2023, Frontiers in Pharmacology

View all citing articles on Scopus

View full text

Mini-reviewMultitargeted therapy of cancer by tocotrienols

Abstract

Introduction

Section snippets

Metabolic fate of tocotrienols

Antioxidant properties of tocotrienols

Anticancer properties of tocotrienols

Tocotrienols and breast cancer

Conclusion

J. Lipid Res.

J. Biol. Chem.

Neurosci. Lett.

BBRC

J. Nutr.

J. Nutr.

Biochem. Biophys. Res. Commun.

Cancer Lett.

J. Biol. Chem.

J. Nutr.

Pancreatology

Biochem. Pharmacol.

Cell

Trends Cell Biol.

J. Biol. Chem.

Nutr. Res.

Free Radic. Biol. Med.

Cancer Lett.

Tocotrienols: vitamin E beyond tocopherols

Life Sci.

The chemistry and antioxidant properties of tocopherols and tocotrienols

Lipids

Vitamin E: non-antioxidant roles

Prog. Lipid Res.

Vitamin E in humans: demand and delivery

Annu. Rev. Nutr.

Pharmacokinetics abd bioavailability of alpha, gamma, and delta-tocotrienols under different food status

J. Pharm. Pharmacol.

Vitamin E: function and metabolism

FASEB J.

α-and gamma-tocotrienols are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine

Lipids

Differences in the plasma transport and tissue concentrations of tocopherols and tocotrienols: observations in humans and hamsters

Proc. Soc. Exp. Biol. Med.

Diet derived and topically applied tocotrienols accumulate in skin and protect the tissue against ultraviolet light-induced oxidative stress

Asia Pac. J. Clin. Nutr.

Vitamin E as in vitro and in vivo antioxidant

Ann. N. Y. Acad. Sci.

Influence of palm oil or its tocotrienol-rich fraction on lipid peroxidation potential on rat liver mitochondria and microsomes

Biochem. Mol. Biol. Int.

Mini-review
Multitargeted therapy of cancer by tocotrienols