Turning Back Cancer’s Clock
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.

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.

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.

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.

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.

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 imwww.ely 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. 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.

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 www.ed 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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