|
LE Magazine May 2002
Page 2 of 3
Tocotrienols and breast cancer
Interestingly, human breast cancer cells have been shown to
respond very well to treatment with tocotrienols.[38-44]
 |
| Tocotrienols show promise as a
natural and safe alternative to risky surgery for
atherosclerotic blockage because of their ability to
reverse carotid stenosis, not merely stop its
progression. |
|
While most breast cancers are believed to be estrogen
dependent, some tumors, particularly postmenopausal tumors, do
not depend upon estrogen for their growth. Anti-estrogen
drugs, such as the widely used tamoxifen, are most effective
on hormone sensitive tumors. The use of tamoxifen is also
limited by the development of resistance to this drug in many
patients.[45] Tocotrienols provide
growth inhibition of breast cancer cells in culture that is
independent of estrogen sensitivity, and have great potential
to be a significant aid in the prevention and treatment of
breast cancer.
A number of in vitro studies have demonstrated the
effectiveness of tocotrienols as inhibitors of both estrogen
receptor-positive (estrogen responsive) and estrogen
receptor-negative (non-estrogen responsive) cell
proliferation.
Researchers tested the effect of palm tocotrienols on three
different cell lines of estrogen responsive and estrogen
non-responsive human breast cancer cells (MCF7, MDA-MB-231 and
ZR-75-1). They found that tocotrienols inhibited cell growth
strongly in both the presence and absence of estradiol, the
major estrogen in the body. The researchers also demonstrated
that tocotrienols enhanced the effect of tamoxifen. The gamma-
and delta-fractions of tocotrienols were most effective at
inhibiting cell growth, while alpha-tocopherol was ineffective
in doing so.[38-40]
Among the tocotrienols, delta-tocotrienol was shown in
another study to be the most potent inducer of apoptosis
(programmed cell death) in both estrogen-responsive and
estrogen non-responsive human breast cancer cells, followed by
gamma and alpha-tocotrienol (beta-tocotrienol was not tested).
Interestingly, delta-tocotrienol is more plentiful in palm
tocotrienols than in tocotrienols derived from rice. Of the
natural tocopherols, only delta-tocopherol showed any
apoptosis-inducing effect, although it was less than a tenth
of the effect of palm and rice delta-tocotrienol.[42]
Similar results were obtained when mammary cancer cells
from mice were studied.[44] While
tocopherols had no inhibitory effect on cancerous cell growth,
alpha, gamma, and delta-tocotrienols effectively arrested the
cell cycle and triggered cell death. Highly malignant cells
were most sensitive to the anti-proliferative effects of
tocotrienols, whereas less aggressive pre-cancerous cells were
the least sensitive.
Tocotrienols were found to be far more effective than
alpha-tocopherol in inhibiting breast cancer cell growth.[41] The tocotrienol concentration
needed was less than 1/20 of alpha-tocopherol in estrogen
responsive cells and less than 1/10 in cells unresponsive to
estrogen. Tocotrienols in combination with tamoxifen were more
inhibitory than either compound alone in both estrogen
responsive and non-responsive breast cancer cells. The authors
pointed out that the synergism between tamoxifen and
tocotrienols may allow for the use of lower doses of
tamoxifen, and reduce its risk of adverse side effects. It is
important to note that further studies are needed before
tocotrienols can be used safely in combination with any cancer
therapy.
Gamma tocopherol and prostate cancer
While alpha-tocopherol has proven to be effective in
inhibiting the growth of prostate cancer cells,
gamma-tocopherol has been found to be more effective. In a
study comparing the inhibitory effect of synthetic
alpha-tocopherol and natural gamma-tocopherol on prostate
cancer cell growth, it was demonstrated that gamma-tocopherol
inhibited cell growth at concentrations 1,000 times lower then
synthetic alpha-tocopherol.[46]
One recent study explored the association of
alpha-tocopherol, gamma-tocopherol and selenium with prostate
cancer. Blood samples were examined from 117 men who had
developed prostate cancer and from 233 matched controls.
Higher levels of gamma-tocopherol were associated with
significantly lower prostate cancer risk. Men in the highest
quintile of gamma-tocotrienol levels had a five-fold reduction
in the risk of developing prostate cancer compared to men in
the lowest quintile. Significant protection by high levels of
selenium and alpha-tocopherol was observed only when
gamma-tocopherol concentrations were high.[47]
The super antioxidant
Much of the broad involvement of vitamin E in human
metabolism is due to its role as the body’s primary
lipid-soluble antioxidant. Tocopherols and tocotrienols are
part of the body’s highly effective defense system,
without which life as we know it could not exist. This defense
system consists of a network of antioxidants, interacting with
and supporting each other. Antioxidants such as vitamin C,
coenzyme Q10 and glutathione are needed for effective
recycling of tocopherols and tocotrienols.
 |
| Much of the broad involvement of
vitamin E in human metabolism is due to its role as the
body's primary lipid-soluble antioxidant. Tocopherols and
tocotrienols are part of the body's highly effective
defense system, without which life as we know it could
not exist. |
|
The unique power of both tocopherols and tocotrienols is
their ability to break the chain reaction of lipid
peroxidation by neutralizing peroxyl radicals to prevent the
spread of free radical damage in cell membranes. Tocotrienols
are more potent scavengers of the peroxyl radical than
alpha-tocopherol and, as we shall see below, provide far
better protection against lipid peroxidation. Peroxidation of
fatty acids (lipids) in cell membranes has a great impact on
both cellular structure and function. Peroxidation of
LDL-cholesterol, for example, is known to be the first step in
the development of atherosclerosis.[48-49]
Lipid peroxidation is destructive, because lipids are an
essential part of cell membranes, hormones and nerve tissue.
The damage itself initiates a chain reaction of free radical
generation. Vulnerable polyunsaturated fatty acids generate
peroxyl radicals, which not only damage lipids, but also
damage important proteins responsible for most daily functions
in humans.
The efficiency of the various vitamin E members is not
equal, however. While gamma-tocopherol is a more effective
antioxidant than alpha-tocopherol, particularly in reducing
damage from nitrogen radicals[50-51], tocotrienols have proven to be
even more powerful than tocopherols. The greater antioxidant
effect of delta-tocotrienol compared to alpha-tocopherol is
thought to be due to its molecular structure, more uniform
distribution in cell membranes, greater recycling activity,
and more effective collision with free radicals.[52]
In one study, the efficacy of alpha-tocotrienol was 40
times higher than alpha-tocopherol in protecting rat liver
microsomal membranes against lipid peroxidation and 6.5 times
higher in protecting cytochrome P-450 against oxidative
damage.[53] Cytochrome P-450 is a
system of enzymes that play a central role in the
detoxification of both exogenous (such as drugs and
pesticides) and endogenous (such as hormones) compounds and in
the synthesis of steroid hormones and bile acids in the
liver.
A follow-up study demonstrated that tocotrienols protect
against injury from ischemia and reperfusion (interruption and
resumption of blood flow) in isolated rat hearts[54]. A mixture of tocotrienols (55%)
and tocopherols (45%) from palm oil was used in this
study.
Following 40 minutes of ischemia, alpha-tocotrienol was
more active in free radical scavenging than alpha-tocopherol
and was preferentially consumed. The recycling efficiency of
alpha-tocotrienol was also higher than alpha-tocopherol, which
may be one reason for its significantly higher physiological
activity under oxidative stress.
An in vitro rat brain study[55]
confirmed the superiority of tocotrienols as inhibitors of
lipid peroxidation. The study also demonstrated that
tocotrienols at low dosage can inhibit protein oxidation in
brain mitochondria. Palm tocotrienols were significantly more
effective than alpha-tocopherol in this study.
Gamma-tocotrienol had the strongest inhibitory effect, while
alpha- and delta-tocotrienols were less effective. These
results suggest that palm tocotrienols may be helpful in
preventing neurodegenerative disorders caused by oxidative
stress. Clinical studies are eagerly awaited.
Another study on rat liver microsomes demonstrated the
ability of palm tocotrienols to protect cell membranes from
oxidative damage. Gamma-tocotrienol again was the most
effective. At the low concentration of 5 uM, palm tocotrienols
significantly inhibited protein oxidation (37%) and lipid
peroxidation (27-30%).[56]
Nitrogen radicals, originating from nitric oxide (NO),
cause severe damage to the body. Nitric oxide is an important
signaling molecule produced in many tissues, including the
blood vessel lining (endothelium) and the brain. It regulates
a diverse range of physiological processes. When superoxide
and NO combine, however, one of the most toxic radicals in the
human body, peroxynitrite, is formed.
Gamma-tocopherol and gam-ma-tocotrienol are the vitamin E
isoforms that have been found most effective in reducing
damage from nitrogen radicals. In contrast to
alpha-tocopherol, gamma-tocopherol has the ability to scavenge
nitrogen dioxide without forming toxic nitrogen products, and
was found to be a more effective inhibitor of cancerous
transformation of cells.[57]
Gamma-tocopherol is also significantly more effective than
alpha-tocopherol in inhibiting peroxynitrite-induced lipid
peroxidation. Another team of scientists demonstrated that
gamma-tocopherol is required to remove peroxynitrite-derived
toxic products, despite the antioxidant action of
alpha-tocopherol.[51] This is an
important discovery as peroxynitrite is one of the major
damaging oxidants produced in humans. Its formation is
particularly associated with ischemic injuries, inflammation
and neurodegenerative disorders. The authors suggest that the
presence of both tocopherols may be required in vivo for
optimal protection against nitrogen radicals.
Indirect support for this argument can be found in a study
showing that plasma levels of gamma-tocopherol (but not
alpha-tocopherol) rapidly increase when long-term smokers stop
smoking. This suggests that mainly gamma-tocopherol is
consumed in combating free radicals produced by smoking. High
doses of alpha-tocopherol have also been shown to displace
gamma-tocopherol in plasma and other tissues.[58]
Tocotrienols and hypertension
|
What is a
Free Radical?
Free radicals are the products
of oxidative reactions in the body. They are highly
reactive compounds that take electrons from other
molecules to stabilize themselves. In this process
of electron “theft”, a new free radical is created,
namely, the molecule from which the electron was
taken. That new free radical then practices “theft”
on another nearby molecule, and a chain-reaction
cycle of cell destruction begins.
It is important to realize
that oxidation is a normal part of life as are
free radicals. Oxidation is what enables us to
get and use energy from our food. When free radicals
are produced in excess, however, they are so damaging
that the body maintains a sophisticated antioxidant
system to hold them in check.
However, when the body’s prolonged
exposure to oxidative factors causes an excessive
output of free radicals that exceeds the body’s
ability to neutralize them (technically called
“oxidative stress”), the body is put in an increasingly
vulnerable position due to accelerated cell destruction.
Antioxidants are substances
that neutralize free radicals.
|
|
An important factor in hypertension and congestive heart
failure is the body’s pool of extra- cellular fluid.
Scientists have for decades searched for the hormone in the
body that controls the release of excess water and thereby
reduces high blood pressure. In 1996 a compound with this
effect was isolated, LLU-alpha, which proved to be a
metabolite of gamma-tocopherol.[59] Last year animal studies indicated
that LLU-alpha also is produced from gamma-tocotrienol.[60-61]
Hypertension has also been associated with elevated lipid
peroxide levels (see the antioxidant section) both in animals
and humans. In a study of tocotrienols in spontaneously
hypertensive rats[62], it was
demonstrated that treatment with gamma-tocotrienol prevented
the development of age-related hypertension by scavenging free
radicals and enhancing the body’s enzymatic antioxidant
defense system. Tocotrienols reduced lipid peroxidation in
blood vessels and significantly increased the activity of the
antioxidant superoxide dismutase (SOD).
The radical scavenging effect of tocotrienols may affect
blood pressure in other ways than through reduced lipid
peroxidation. Earlier studies showed that free radicals can
inactivate nitric oxide (NO) to impair vasodilatation, which
leads to an increase of peripheral resistance and blood
pressure. We look forward to further research in this
area.
The need for full spectrum vitamin E
Vitamin E has an excellent safety record.[63-66] However, studies of
alpha-tocopherol alone, without the mix of other tocopherols
and tocotrienols, has shown pro- oxidant rather than
antioxidant activity in people consuming high doses (over 1000
mg).[67]
We have seen that the various vitamin E forms have their
unique role in the metabolism of the human body. Research
strongly suggests that we need the full spectrum of vitamin E
to maximize our chances of preventing and, possibly, treating
many of the diseases of aging.
References on Page
3 of 3
Back to
the Magazine Forum
|