Inositol Hexaphosphate
Turning Back Cancer's Clock
January 2000 Newsletter
by
Kimberly Pryor
The statistics are staggering. Last year in the United States, 563,100 people
were expected to die of cancer—more than 1,500 people a day. Cancer is the
second leading cause of death in the United States, exceeded only by heart
disease. These statistics translate into a very real threat to us all.
For the past
two decades, scientists have looked upon fiber almost as a panacea in the
battle against cancer, particularly colon, mammary and prostate cancer. The
nightly news has bombarded viewers with the latest research outlining fiber’s
protective role. Even the marketing divisions of cereal and oatmeal
manufacturers jumped on the bandwagon, touting the fiber versus cancer
studies in their advertisements. However, recent research reveals that
scientists may have been led astray when it comes to the cancer-inhibiting
benefits of dietary fiber. As new studies unfold, researchers are beginning
to realize that there is an additional substance in dietary fiber that adds
to its powerful effects against cancer. This heretofore little-known
substance is a component of fiber called inositol hexaphosphate, also known
as InsP6, IP6 or phytic acid.
IP6 occurs in
foods that are rich in fiber—especially cereals and wheat bran, along with
corn, soy beans, nuts (especially peanuts), oats, seeds and rice. IP6 has
traditionally been considered an antinutrient due to its ability to interfere
with the body’s absorption of minerals such as iron, calcium and zinc.
However, scientists have recently discovered that IP6 is a powerful
antioxidant and chemopreventive agent.1-3
Researchers
initially overlooked IP6 because it was obscured by its dietary carrier—fiber.
Fiber is an important part of the anticancer arsenal. Scientists estimate
that up to 70% of all cancer is attributed to diet.4 The typical low fiber
Western diet has been linked to the development of colon, prostate and
mammary cancers.5-6
For example,
in the U.S., the rates of prostate cancer and postmenopausal breast cancer
are 26 and 10 times higher than in China, respectively—a difference possibly
due to the fact that Americans consume almost three times less cereal than
the Chinese.7 In addition, one study of 37 countries found a link between
high intake of cereal grains and low rates of colon cancer;8 and researchers
at the George Washington University Medical Center discovered that wheat bran
alone, or wheat bran plus psyllium, inhibits earlier phases of
carcinogenesis.9
These studies
are in contrast to other studies, however, which found no direct link between
fiber consumption and colon cancer. For example, Danes have a much higher
incidence of colorectal cancer than Finns, although both groups consume
approximately equal amounts of dietary fiber. This variance between studies
suggests that fiber isn’t the sole factor responsible for the inhibition of
carcinogenesis. Researchers are beginning to suspect that IP6 may be even
more potent in preventing cancer than the fiber in wheat bran. Scientists
determined that although both Scandinavian populations consume equal amounts
of fiber, the lower-risk Finns consume food items with 20-40% more phytic
acid (IP6) than the higher-risk Danes (Fig. 2).10-11
IP6’s Role
IP6—along with its lower phosphorylated forms, especially IP5—is present in
virtually all mammalian cells.12 It is an offspring of the nutrient inositol,
and consists of a myo-inositol ring and six symmetrically distributed
phosphate parts [Fig. 1].
Scientists
have confirmed IP6’s existence within cells, but its primary purpose is still
unknown. Although IP6 has been called one of nature’s most powerful
antioxidants, its role appears to be far more extensive. It has been
suggested that IP6 can regulate heart rate and blood pressure, and may also
serve as a neurotransmitter.13-16
Because IP6 is a highly charged molecule, scientists formerly thought it could
not be transported inside the cell, and believed that absorption by organisms
was impossible. The fact that IP6 might work intracellularly was also
discounted. However, preliminary work began to indicate otherwise. In vitro
studies show that malignant cells almost immediately begin accumulating IP6
intracellularly. Scientists also found that IP6 is absorbed through the
stomach and upper small intestine within one hour after administration.
When cells
accumulate IP6, something remarkable happens. Unlike most other anticancer
agents, IP6 turns back the clock on the malignant cells, forcing them to
revert to a non-cancerous state. This phenomenon has been observed in HT-29
human colon carcinoma cells. Malignant and premalignant cells of the colon
and other epithelial cells express the tumor marker D-galactose-ß-[1
‘3]-N-acetyl-D-galactosamine; this marker is absent on normal cells.
Following IP6 treatment of malignant cells, the tumor marker was
significantly suppressed, and in most cells the marker was completely absent.
IP6 also caused a decreased rate of cell proliferation.17-18
Proposed
Anticancer Mechanisms
IP6 exerts its effects on the body by controlling cell division. IP6 reduces
the rate of cellular proliferation, both in vivo and in vitro, and has exhibited
an ability to reduce DNA synthesis.19-21 Scientists have suggested that one
way IP6 may exert this cellular control is by interfering with mineral
absorption, since iron and other minerals are important in gene regulation.22
Studies have shown a possible link between excess iron and an increased risk
of cancer in animals and humans, particularly colon cancer.23 IP6 has been
shown to interfere with iron absorption and reverse iron-dependent
augmentation of colorectal tumorigenesis. IP6 also suppresses iron-catalyzed
oxygen generation, and almost totally inhibits iron-catalyzed lipid
peroxidation.24-25
A concern in
this regard, of course, is the possibility that IP6 may deplete the body’s
mineral stores. In numerous studies, researchers have noted no significant
differences in the level of serum or bone minerals in rats, even after
lengthy treatment with IP6 and inositol.26
AbulKalam
Shamsuddin, MD, PhD, has extensively studied IP6. In a 1997 Life Sciences’
article, Shamsuddin stated that “Certainly, its [IP6’s] hypothetical harm
connected to chelation is far less than that of other compounds of similar
usage (eg. cancer chemotherapeutic and chemopreventive agents) and are far
outweighed by the plethora of benefits.”
The questions
that arise in regard to IP6’s ability to chelate minerals suggests that other
anticancer actions are at play. These actions include:
·
Boosting natural defense mechanisms. Natural killer (NK)
cells defend the body against tumor initiation. Studies have shown that mice
with carcinogen-induced tumors, when treated with IP6, demonstrate augmented
NK activity over the untreated controls.27
·
Inhibiting carcinogenesis through the “lower IPs.” Scientists believe
that IP6’s actions may be mediated through lower forms of the molecule. One
study by Shamsuddin showed that after IP6 treatment of K-562 human
erythroleukemia cells, there was a 41% increase in intracellular IP3 and a
26% decrease in IP2. This alteration in the cellular inositol phosphate pool
may indicate that the evolution from IP6 to lower forms of the molecule is a
crucial step in the inhibition of carcinogenesis.28
·
Blocking PI-3 Kinase. PI-3 Kinase is an enzyme necessary for tumor
promotion; a normal cell requires PI-3 Kinase to become cancerous.
Researchers have found that IP6 is a profound inhibitor of PI-3 kinase.29-30
·
Altering cellular communication necessary for tumor growth. Proteins called
fibroblast growth factors (FGF) initiate conversations between cells. Each
FGF possesses a transmitter and receiver. As these cellular conversations
occur, sugar molecules called heparan sulfates intercede to modulate the
messages, flowing back and forth via the FGF system. It is through this
process that a very specific type of heparan sulfate works in different
tissues to maintain proper function and control cell division. Fibroblast
growth factors have been implicated in tumor cell growth, as certain cancer
cell lines have been shown to express FGF binding sites. IP6 mimics one
specific part of the long heparan sulfate chain, thereby interfering with the
functioning of the entire heparan sulfate molecule, suppressing DNA synthesis
and cell division induced by FGFs.31-32
·
Stimulating the p53 gene. If the tumor suppressor gene p53 is not
functioning, cancer cells become more resistant to chemotherapeutic agents.
IP6 has been shown to up-regulate the expression of p53.33
Colon
Cancer
In 1988, Shamsuddin reported in the journal Carcinogenesis the stunning
effect IP6 had on large intestinal cancer in rats. Researchers fed 1% sodium
inositol hexaphosphate (Na-IP6) to one group of animals one week prior to
inducing cancer, and to another group two weeks after the last dose of a
carcinogen was administered. Rats who took the IP6-laced drinking water prior
to carcinogen treatment exhibited a 35% decrease in large intestinal cancer
compared to the control carcinogen group. The group fed IP6 after receiving
the carcinogen showed a similar reduction.34
In 1989, Shamsuddin and colleagues fed rats 2% IP6 in drinking water five
months after induction of carcinogenesis. Compared to untreated rats, animals
on IP6 had 27% fewer tumors and the tumors were approximately two-thirds
smaller in size. This suggests that IP6 may be important in both the
treatment and prevention of cancer.35
Phytic acid (IP6) was also effective at reducing the incidence of colon
tumors in conjunction with a high risk, high fat diet. The incidence of colon
tumors in carcinogen-treated rats plummeted from up to 70% in the control
groups to 30% in the groups fed a high risk diet (HRD) plus phytic acid.36
Pretlow and colleagues (1994) demonstrated that IP6 is an even more powerful
chemopreventive agent than selenium in halting the development of colon
carcinogenesis.37
Breast
Cancer
Diets high in fat and iron have been linked to an increased risk of mammary
cancer. In clinical studies, IP6 has mitigated the dangerous consequences of
a high fat diet. Dietary administration of phytic acid (2%) in conjunction
with carcinogens and a HRD led to a significant reduction in the incidence of
mammary tumors in rats compared to those consuming only the HRD. Twenty-one
weeks after administration of the carcinogens and the HRD, the incidence of
mammary tumors in the HRD plus phytic acid group was reduced by up to
50%.38-39
IP6 has been
shown to inhibit carcinogenesis in all types of mammary cancer cells—those
that require estrogen for growth and those whose growth is independent of the
female sex hormone. It accomplishes this by inhibiting DNA synthesis and cell
growth, and inducing differentiation of the cancer cell lines.40-42
Other
Cancers
In vivo and in vitro studies have shown that IP6 has a protective effect
against lung, liver, prostate and skin cancers.
·
Prostate Cancer - Shamsuddin noticed a significant
dose-dependent growth inhibition in human prostate cancer cells in vitro. As
early as three hours after treatment and continuing up to 48 hours, IP6
suppressed DNA synthesis in prostate cancer cells.43
·
Hepatocellular Carcinoma - Patients suffering from Hepatocellular
carcinoma (HCC), a common liver cancer, usually have an extremely poor
prognosis. Studies indicate that IP6 may be an important treatment for this
disease. In the first of two experiments, Shamsuddin and colleagues compared
the in vitro effects of IP6 on HepG2, a human liver cancer cell line.
Compared to other cancer cell lines, HepG2 cells were extremely sensitive to
IP6, experiencing a dose-dependent, 50% inhibition of cell growth. IP6 also
weakened HepG2’s ability to form colonies. The sequel to the experiment
demonstrated that IP6 can regress pre-existing human liver cancer cells
transplanted in mice back to their normal, non-cancerous state. In addition,
the tumor weight in IP6-treated mice was 86% to 1180% less than that in
control mice.44-45
·
Lung Cancer and Asbestos-Induced Fibrosis - Scientists have
also received positive results with IP6 in regards to lung cancer and
asbestos-induced fibrosis and carcinoma. Studies have shown that fibrosarcoma
cells in mice treated with IP6 resulted in a significant inhibition of tumor
and size as well as improvement of survival over the untreated controls.
Similar treatment with IP6 of mice with experimental lung metastasis resulted
in a significant reduction in the number of metastatic lung colonies. Due to
its antioxidant properties and its ability to chelate iron, IP6 diminishes
the asbestos-induced oxidative damage that results in inflammation and
fibrosis in the lungs of exposed animals, from six to 30-fold less than in
control groups.46-47
·
Skin Cancer - In a pilot study of mouse skin carcinogenesis, Zarkovic
and colleagues reported that IP6 prevented skin papillomas when given during
cancer initiation. After initiation however, IP6 exerted little effect. In
regards to skin cancer, scientists are calling for more studies to determine
IP6’s effectiveness in patients who have already been diagnosed with the
disease.48
·
Rhabdomyosarcoma - IP6 has suppressed the growth of
rhabdomyosarcoma, the most common soft tissue sarcoma in children. Cell line
growth was reduced by 50% in vitro in a dose-dependent fashion. After two
weeks, IP6 treated mice experienced 25-fold smaller tumors and a 49-fold
reduction in tumor size after five weeks.49
Kidney
Stones, Platelet Aggregation, Heart Attacks and HIV
A multifaceted nutrient, IP6 has been shown to benefit a number of other
conditions. Researchers at the Harvard Medical School and Massachusetts
General Hospital in Boston successfully used pure Na-InsP6 to treat
idiopathic hypercalciuria, which is associated with a high incidence of
kidney stones.50
Other
research points to IP6’s usefulness in preventing platelet aggregation—a
prime cause of heart attacks and strokes. In one study, IP6 inhibited
platelet aggregation by 45% in an in vivo animal model. An in vitro study by
the same researchers, stickiness was induced in human whole blood taken from
healthy volunteers. IP6 reduced clotting by 50%, or eliminated it
altogether.51
Other
research points to IP6’s role in controlling the damage inflicted upon the
myocardium (heart muscle) during heart attacks. After a heart attack, doctors
reperfuse (fill) the heart area with oxygenated blood. This poses its own set
of risks, because the oxygen can churn out free radicals, damaging the blood
vessels and heart muscle. Researchers successfully used IP6 to protect the
heart muscle from superoxide damage during reperfusion.52-53
As more
studies unfold, additional properties of IP6 have been revealed. Otake and
colleagues demonstrated that IP6 inhibited the cell destruction induced by
HIV as well as the HIV specific antigen expression. IP6’s ability to boost
natural killer cells could have future implications for AIDS sufferers.54
Synergistic
Effect
In his book, IP6: Nature’s Revolutionary Cancer Fighter, Shamsuddin, calls
IP6 combined with inositol, “an anticancer cocktail.” IP6 combined with
inositol exerts an even more powerful suppression of cell proliferation and
colorectal cancer than with either agent alone. This potent “cocktail” has
also been used to suppress carcinogenesis in mammary and metastatic tumor
models. Other studies point to the synergistic effect of green tea and phytic
acid. When scientists combined these two substances, they had a significant
impact on precancerous lesions in rats.55
Dietary
IP6 Less Effective
When administered in the diet, IP6 binds with proteins, forming insoluble
complexes that are less readily metabolized and absorbed. Because IP6 is
particularly abundant in the bran part of certain mature seeds such as wheat,
one group of scientists investigated whether a high-fiber bran diet
containing high IP6 inhibits rat mammary carcinogenesis induced by
7,12-dimethylbenz[a]anthracene (DMBA). Rats were fed a diet containing, 5%,
10% or 20% Kelloggs’ All Bran; another group received 0.4% IP6 in drinking
water equivalent to that in 20% bran. The fifth group served as the control.
After 29 weeks, compared with the carcinogen control, tumor incidence was
reduced by 16.7%, 14.6% and 11.4% in rats fed 5%, 10% and 20% bran,
respectively, not an insignificant amount. However, rats fed 0.4% IP6 in
drinking water had a whopping 33.5% reduction in tumor incidence and nearly
50% fewer tumors.
Researchers
stated: “Thus, IP6, an active substance responsible for cereal’s beneficial
anticancer effect, is clearly more effective than 20% bran in the diet.
...Intake of IP6 may be a more pragmatic approach than gorging enormous
quantities of fiber for cancer prophylaxis.”56-57
Safety of
IP6
The majority of clinical studies have confirmed the safety of IP6. Shamsuddin
and colleagues witnessed no adverse effects on body weight, serum mineral
content or any pathological changes of consequence after administering IP6 to
F344 or female Sprague-Dawley rats for 40 weeks. The safety of IP6 has also
been confirmed in human studies. Researchers at Harvard Medical School and
Massachusetts General Hospital administered pure Na-InsP6 orally to 35
patients at a dose of 8.8 grams (!) per day in divided doses for an average
of 24 months. The patients showed no signs of any toxic reactions.
Furthermore, researchers have noted that the cell division rate of healthy
animals receiving IP6 shows no deviation from the normal.58-60
Conclusion
There is admittedly a dearth of human clinical studies confirming the
potential cancer-fighting effects of IP6. Nevertheless, there are certainly
ample theoretical reasons why it should be effective, as well as a number of
in vitro and in vivo studies that document its ability to normalize cancer
cells and reduce tumors in experimental animals. Furthermore, there are
animal and human studies confirming the absolute safety of IP6. Consequently,
in view of the evidence for potentially great benefit and total lack of
toxicity, rather than wait years for further human double-blind placebo
controlled studies to be performed, we believe that IP6 should be considered
an absolutely essential element in any broad spectrum nutritional cancer
preventive or therapeutic program.
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