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The Role of IP6 in Cancer Prevention

by Marcus Webb,(more info)

listed in cancer, originally published in issue 81 - October 2002

Introduction

Even the word cancer sends chills down the backs of most people. It must be the most dreaded of all diagnoses, since its treatments often involves very unpleasant and sometimes drastic medical measures. However, cancer is treatable. Modern chemotherapy is getting more targeted with the development of 'smart' drugs that home onto the tumours leaving healthy tissue alone. Targeted chemotherapy is obviously the medical way forward, but one must ask the question: are we leaving things too late once a tumour has formed? Is there no way to detect cancerous changes before tissue changes can be seen physically or prevent these pre-cancerous changes happening in the first place?

microscopic image

I have been searching for the answers to these questions for years, as have many other cancer researchers I am sure. It was these questions that led me to make contact with Dr Shamsuddin, MD, PhD, a Professor of Pathology at the University of Maryland School of Medicine. I was very interested in his work with markers (from rectal mucus) for pre-cancerous changes. In the laboratory the mucus sample can be treated with the enzyme galactose oxidase, then stained with Schiff's reagent. This produces a colour change. The test is based on the expression of a specific glycoprotein (gal-galNAc) by the pre-cancerous cells only when their molecular machinery changes prior to a morphological change that is characteristic of cancer. This test answered one of my questions: can we detect cancer before we can see it? However, Shamsuddin also offered the answer to my other question: can we prevent it starting in the first place? To this question he supplied me with the research and supporting data on inositol hexaphosphate (IP6 for short). Since then, we have become good friends, meeting up at scientific conventions and working together to further the paradigm shift that is required to incorporate the use of early pre-cancerous markers and chemopreventative agents in the fight against cancer.

Cancer Affects People Not Lab Rats

In my particular line of work, I see many patients with end-stage cancer; those who have been through the medical mill and sadly have not responded well or are simply too ill to cope with the treatment. Some days can be heartbreaking, with patients and their attendant family members looking for any magical last hope. As any holistic practitioner will tell you, we deal with whole person therapy and our methods do not necessarily focus on the specific illness since the holistic paradigm incorporates the mind, body and spirit. Despite this being something in which our medical colleagues are now taking an active interest (in the guise of psycho-neuro-immunology), it is still an area poorly covered in conventional cancer care.

The holistic management of cancer patients can present somewhat of a dilemma to practitioners of complementary medicine. On the one hand, we have an ever-expanding wealth of evidence-based medicine to confront surrounding the established use of chemotherapy, radiation and surgery, while on the other we can't turn our backs on the fundamental principles of the holistic approach. The former president of the British Cancer Council summed up the situation nicely: "Cancer is no more a disease of cells than a traffic jam is a disease of automobiles. Both traffic jams and cancer are problems of the ecology - of an entire organism, in the case of the city, of the whole person, in the case of cancer." (R D Smithers, 1971).

Holistic practitioners are no strangers to the mind-body axis. Even Galen noted that breast cancers occurred more often in women with a 'melancholic' rather than a 'sanguine' temperament. However, times have moved on and a more evidence-based approach is demanded for twenty-first century health care. This can be seen when it comes to cancer, since there has been much written on the effects of emotional well-being and the immune system,[1-5] a system known to be at the heart of many cases of cancer, especially in the case of the so-called natural killer (NK) cells.[6] Immune support can, therefore, be seen to form the foundations of a holistic programme for cancer sufferers. Just how the various herbal and nutritional remedies recommended by practitioners interact with conventional chemotherapy still remains a stumbling block for the effective integration of complementary methods with mainstream medicine, despite in-depth reviews of the subject.[7]

New Times and New Ways

There is no avoiding it; the molecular age is upon us. Gene codes and the new information deciphered from the human genome promise to open the doors to disease control and cure, but how far forward are we really? Modern genetic testing may be able to detect regions of defective DNA and predict the clinical outcome, but we are no further on in offering a cure. Gene splicing, or replacing regions of damaged DNA with the correct sequence, is still a 'Star Trek' concept for molecular biologists, but it happens within every cell of our body on a daily basis. It is this ability of our cellular machinery to self-correct defective parts of its replication mechanism that keeps us healthy and free of the devastating consequences of genetic mutation. By this I don't mean that we are going to grow two heads, but rather that the genetic damage that our DNA receives on a daily basis from such sources as ultraviolet (UV) radiation and intrinsic and extrinsic free radical production, to name a few, physically disrupts the delicate genetic sequences that code for every hormone, protein and bodily function that keeps us alive and well. Each of these damaging strikes hits to the core of our very being; our DNA.

Genes, Amino Acids and the Fundamentals of Life

We have Watson and Crick to thank for the discovery of DNA, or so we have been led to think! Even though it's rather academic, the race to discover the exact amino acid sequence and structure of DNA was a very closely run battle with all the players gaining insight and inspiration from one another. It was only an unfortunate slip in some basic chemistry that threw Linus Pauling off the mark, allowing the Cambridge-based team of Watson and Crick to publish their findings first in 1953. Anyone interested in the race to discover DNA should read James Watson's book Genes, Girls and Gamow[8] for the full story. However, thanks to the work of many scientists and the definitive publications of Watson and Crick, we were provided with the genetic code, in the form of specific amino acid sequences that coded for the fundamentals of life. There is no getting away from the fact that this was probably one of the greatest discoveries of all time, but even this important discovery had some antecedents that required some impressive powers of inspired thought and insight. At the start of this century a gifted German embryologist named Theodor Boveri predicted that cancer started in a single cell. This process was a direct consequence of changes or imbalances that he observed in genetic information during experiments on sea urchin embryos. This finally led him to believe that the defects that cause cancer must reside in the chromosomes of cells. Like all original thinkers, his novel ideas did not go down well with the establishment of his time and it is only now that we recognize the true magnitude of his concept.

Cancer and its causes have always fascinated scientists. In the 1920s, work at the Institute of Cancer Research in London discovered the world's first carcinogen - polycyclic hydrocarbons. These substances are responsible for the cancer causing properties of coal tar. The 1920s would appear to have been a good year for carcinogens, since Hermann Muller also confirmed that ionizing radiation was a cause of cancer, a fact that we all now take for granted.

It was only relatively recently (by the 1960s) that work from the Institute of Cancer Research showed that carcinogenic substances, like coal tar, reacted directly with the DNA, not RNA or proteins as was previously suspected. This landmark brings us back to Watson and Crick who, only seven years previously, elucidated the structure and function of DNA. It was thanks to their work that molecular biology was born and with it the discovery of cancer causing genes (oncogenes) and our molecular policemen, the tumour suppressor genes.

Good Communication - the Basis of a Healthy Life

The ability to communicate is of paramount importance in our society. Voicing opinions, reading texts or viewing images all form key stages in deciding in what direction our lives should go. Simply take away our senses and we soon spiral into a state of confusion and disorientation. Now translate this concept to a cellular basis. Most of the body's cells live in darkness and rely on an elegant system of chemical messengers to inform them of what is going on around them. Cell-to-cell communication, often termed cell signalling, is a subject that has become a keen area of biomedical research. One area where defects in cell communication commonly occur is in cancer. Take, for example, the key stages in the cell cycle.

These stages all require a well-orchestrated set of communications to function correctly. Disrupt one of these and disorganized cell reproduction occurs during which DNA transcription defects can be reproduced within each and every daughter cell. In time, a single cell defect can multiply into thousands of mutated daughter cells, all of which enter a defective cell cycle yielding millions more. It is only when defective cell multiplication has run long enough for a mass of cells to accumulate into a visible tissue change that cancer can be physically diagnosed.

The phases of the cell cycle can be divided up into four distinct stages. The M phase represents the stage of cell multiplication by the process of mitosis. This stage is followed by the G1 (gap 1) phase, corresponding to the interval between mitosis and the initiation of DNA replication. During the G1 phase the cell is metabolically active and continuously grows but does not replicate its DNA, however DNA repair can occur. The G1 phase is followed by the S (synthesis) phase during which DNA replication takes place. The completion of DNA replication is followed by the G2 (gap 2) phase when the cell grows and proteins are synthesized in preparation for mitosis (see Figure 1).

The duration of these cell cycle phases varies from cell type to cell type, with a typical cell cycle taking 24 hours during which the G1 phase accounts for 11 hours, the S phase about 8 hours, the G2 phase about 4 hours and the M phase about 1 hour.

In addition to the G1, S, G2 and M phases, some cells from certain tissues such as the liver, kidney and lung enter a phase of inactivity known as G0 after they exit the G1 phase. During this resting phase the cells remain metabolically active but do not proliferate unless acted upon by the appropriate extracellular signal.

Being able to halt mutant cells early on in the cell cycle (around G0/G1) or being able to detect damaged DNA before it has the chance to replicate itself are the key functions of tumour suppressor genes such as p53. The p53 gene product (a protein) regulates both cell cycle progression and programmed cell death (apoptosis). Its absence prevents damaged DNA being given time to become repaired during the G1 phase of the cell cycle. This lack of repair commonly causes an increased frequency of mutations and instability of the cell's genome. Instability of this type is a characteristic property of cancer cells and may contribute to further alterations in oncogenes and tumour suppressor genes during tumour progression.

Cells lacking p53 fail to undergo apoptosis in response to agents that damage DNA, including radiation and many drugs such as chemotherapeutic agents used to treat cancers. This fact may explain why some cancers appear to be very resistant to conventional therapy.

Polyphosphorylated Carbohydrates - the Key to Healthy Cell Communication

When we look to large-scale epidemiological studies it becomes apparent that diet plays a key role in the progression or start of human cancers. What appears to feature in all the diet regimes associated with a low cancer incidence is the high consumption of fruit, vegetables and high-fibre foods. If we then look a little deeper, we discover that one of the main anti-cancer agents found in many these foods, especially whole grains and legumes, is the polyphosphorylated carbohydrate known as phytic acid. However, naturally occurring phytic acid is often complexed with calcium, magnesium or potassium salts, making it unavailable to the body. One of the key workers in the field of phytic acid and cancer showed that by making pure phytic acid (chemically known as inositol hexaphosphate or IP6 for short) available to the body in higher concentrations than would normally be found in the diet had very beneficial effects on the mechanism of cancer formation (see Figure 2).

Shamsuddin proved that pure IP6 was a highly bio-available substance and was rapidly taken up by active cancer cells. What's more, Shamsuddin went on to show that IP6 was more effective that natural phytic acid in helping to control the progression of an existing cancer condition. In a key paper, Shamsuddin revealed that rats fed with a diet supplemented with IP6 showed a 50% reduction in the number of tumours compared with rats eating a standard high-fibre diet.[9] The implications of these findings suggested that a purified extract of dietary fibre somehow assisted the body in fighting cancer and even caused the regression of existing cancerous swellings.

Studies into the biological effects of IP6 soon revealed that it was a related inositol phosphate, IP3 (inositol triphosphate), that was at the heart of the cellular mechanisms responsible for the remarkable effects seen in cancer models and the animal experiments. IP3 is formed naturally in the body but its concentrations can be elevated by the administration of IP6 via the process of dephosphorylation (the removal of phosphate [PO4]) within the cell (see Figure 3).

When IP3 levels are low (as in cancer cells), the cells appear to replicate in an uncontrolled manner, and normal cell communication is lost. The addition of IP3 literally turns off this process and helps to reset the cell cycle. Shamsuddin soon discovered that by combining the pure IP6 with the correct amount of the B vitamin inositol he could make cells produce two molecules of IP3, which in turn activated the NK cells and other anti-cancer mechanisms (see Figure 4). This method of combining IP6 with inositol at the exact ratio formed the basis of his now patented formulation.[10]

When compared with conventional chemotherapy, which works by killing cells indiscriminately with all the toxic side effects associated with such a mechanism, IP6 can be viewed as a naturally selective agent since it targets cells with abnormal rates of turnover, leaving healthy cells alone. One of the interesting developments involving IP6 is its link to the tumour suppressor gene known as p53.[11] This protein is produced by cells and acts as a cellular policeman that continuously checks for areas of damaged DNA, which could cause mutated cells to replicate themselves with disastrous consequences. Mutations in the p53 gene, making it inactive, are now well accepted as a cause of many cancers, since cells containing damaged DNA are allowed to pass through the cell cycle undetected and liberate daughter cells with the same DNA damage. In time, this causes a cancer to form. Modern molecular techniques are looking for ways to enhance p53 in those who appear to be unresponsive to chemotherapy. Such individuals also appear to have the defective gene for p53 formation. Shamsuddin has already shown that IP6 enhances p53 gene expression, which was associated with a reduction in cancerous cell proliferation and enhancement of cell maturation and differentiation.[11] All of these cellular changes are characteristic of a return to normal from an active cancerous state.

As the data accumulate, IP6 appears to be a very safe and well tolerated adjunctive agent to chemotherapy that may have profound long-term benefits for those in remission or recovering from cancer. A new study is currently under way in the Department of Pharmacology and Molecular Biology at the University of Hertfordshire, where it is hoped that the relationship between IP6 and the tumour suppressor gene p53 will be elucidated further.

Change Your Ways or Die - Getting Heavy with Bad Cells!

The body has many built-in mechanisms to make sure that any cell that does not conform dies. Such rebellious cells are either 'taken out' by the killer cells (NK cells) or undergo cell suicide (programmed cell death or apoptosis). This approach to keeping the body healthy on a cellular basis works incredibly well when you consider that the average human is made up of 40 trillion cells, any one of which has the potential to go 'bad'!

Many cancers occur due to a problem in recognizing when the DNA has become mutated. If this enters the cell cycle and the checking mechanisms are missing or defective (p53 for example), cancers soon follow. This ability to check DNA came under study last year, when cells from human breast cancers (both oestrogen receptor positive and oestrogen receptor negative) were treated with IP6. The results of this experiment clearly showed that both cell lines responded to IP6 in the same way, indicating that it was irrelevant what type of oestrogen receptor status they displayed. This result confirmed the theory that cancer cells and tumour progression can be affected by regulating how cells progress through the cell cycle. IP6 was shown to exert a controlling effect on the progression of cells through the cycle by decreasing the time spent in the S phase and arresting the cells in the G0/G1 phase during which they can repair their damaged DNA or undergo apoptosis. What makes this finding even more exciting is the ability for IP6 to target cancerous cells while leaving healthy cells to pass through the cycle unimpeded. Such selective abilities suggest a part for IP6 in the active holistic management of cancer as well as in the proactive prevention of disease in those with a family history or at high risk.[12]

Killer Cell Activation

It comes as no real surprise that an effective immune response is vital to health and important in controlling the progression of cancerous disease. One specific arm of the immune system, the NK-cytotoxic killer cells, appears to play a pivotal role in cancer. Enhancing the cytotoxic arm of the immune response would appear to be an obvious therapeutic tactic, despite modern oncology bombarding the body with highly toxic chemotherapeutic agents. When NK cells are activated, as in a study looking into the effect of IP6 on colon cancer, it is clear that carcinogenesis is inhibited. The cell line tested was a murine line of NK cells whose activity was decreased in the presence of a potent colon carcinogen known as 1,2-dimethylhydrazine (DMH). In the mice treated with IP6, the effects of DMH were reversed and NK cell activity was increased. The resultant activation of NK cells was associated with a reduced number of DMH-induced colon cancers. In the same experiment, the addition of inositol potentated this effect further. Such effects on immune health and strength can only benefit those with established tumours and help to offset the immuno-suppressive effects of aggressive chemotherapy treatments.[13]

Human Clinical Testing – the Way Forward

All the information presented in this brief review is interesting and thought provoking, but it does not satisfy the sceptics who ask for results of clinical trials. This aspect of evidence-based research also throws up many ethical barriers such as the moral dilemma of exposing patients to a placebo treatment. Knowingly giving a patient a powder of nothing when we have enormous experimental and anecdotal evidence supporting the effectiveness of IP6 in cancer care presents a great problem.

Despite all the problems, we are on the brink of discovering the outcome of a pilot clinical trial carried out at the Department of Surgery in the University of Split in Croatia. By the time that the paper is presented at the seventeenth meeting of the European Association for Cancer Research in Granada, Spain, the trial should include seven patients. The patients have been treated for colorectal cancer using the Mayo protocol for chemotherapy with the addition of 12 capsules of IP6 with inositol daily for the first six months and nine capsules daily thereafter. The initial findings are very encouraging, with most chemotherapy side effects being minimized. At the time that the abstract was released, the investigators concluded that for patients with colorectal cancer of advanced stages the combination of chemotherapy and IP6 with inositol was improving the patients' quality of life and prolonging survival times.

You can follow all the new developments on the IP6 website (www.AboutIP6.com), where the proceedings from the European Association of Cancer Research's seventeenth meeting will be published. This scientific meeting was held in Granada, Spain, in early June. IP6 was well represented with five poster presentations. We will post updates on our own UK laboratory work and related clinical and bench studies from around the world.

Conclusion

In closing this article on approaching cancer from a new perspective, I am very aware that comments pertaining to the treatment of cancer often send shivers through the spines of complementary health practitioners and journal editors alike. Why is this? Is it simply because the Medicines Act states that it is an offence to 'treat' cancer by non-medically qualified persons, or are we more concerned that we are not doing the best for our patients by offering an alternative to the conventional? After all, cancer is normally associated with a dying patient. The medical sceptics are quick to pull on our lack of evidence-based studies, while many in the complementary medicine arena are only too happy to treat patients with outmoded methods with an almost religious conviction. The recently published book Living Proof[14] details the life-changing events surrounding the Oxford Professor Michael Gearin-Tosh. His illness memoirs bring home what we are actually trying to do in clinical practice: treat people and treat them as individuals. Gearin-Tosh was diagnosed with myeloma, a cancer that carries a very poor prognosis, with death within a year of diagnosis commonplace. With medical treatment, death may occur in three years! Not to give too much away for those who may want to read this book, but Gearin-Tosh turned his back on convention and is still alive and very well almost eight years later. Read into this what you may.

I have stolen my final comments from a great hero of mine, the late Carl Sagan. Carl was viewed as somewhat of a maverick in the cosmology world. He was eminently well qualified and a key scientist for the early Viking missions, but he never received the scientific community's acceptance because of his desire to look 'out side the box' and dare to voice his own thoughts. I will leave you with some of his words, spoken at a 1997 lecture entitled 'The Burden of Scepticism':

"It seems to me that what is called for is an exquisite balance between two conflicting needs: the most sceptical scrutiny of all hypotheses that are served up to us and at the same time a great openness to new ideas...If you are only sceptical, then no new ideas make it through to you...On the other hand, if you are open to the point of gullibility and have not an ounce of sceptical sense in you, then you cannot distinguish the useful ideas from the worthless ones."

References

1. Cousins N. Head First. Dutton. Delta. New York. 1989.
2. Pelletise J. Mind as Healer, Mind as Slayer. Delta. New York. 1992.
3. Locke S and Colligan D. The Healer Within: the New Medicine of the Mind and Body. New American Library. New York. 1987.
4. Borysenko J. Mending the Body, Mending the Mind. Bantam. New York. 1988.
5. Watkins A and Jonas W. Mind-Body Medicine. Churchill Livingstone. 1997.
6. Ben-Eliyahu S, Page GG, Yirmiya R and Shakhar G. Evidence that stress and surgical intervention promote tumour development by suppressing natural killer cell activity. Int J Cancer. 80(6): 880-88. 15 March 1999.
7. Lamson D and Brignall M. Antioxidants in cancer therapy; their actions and interactions with oncologic therapies. Alternative Medicine Review. 4(5): 304-29. 1999.
8. Watson JD. Genes, Girls and Gamow. Oxford University Press. ISBN 0-19-850976-6. 2001.
9. Vucenik I, Yang GY and Shamsuddin AM. Comparison of pure inositol hexaphosphate and high-bran diet in the prevention of DMBA-induced rat mammary carcinogenesis. Nutrition and Cancer. 28(1): 7-13. ISSN: 0163-5581. 1997.
10. Shamsuddin AM. IP6: Nature's Revolutionary Cancer Fighter. Kensington Health. New York. p28-36. ISBN 1-57566-357-0. 1998.
11. Saied IT and Shamsuddin AM. Up-regulation of the tumor suppressor gene p53 and WAF1 gene expression by IP6 in HT-29 human colon carcinoma cell line. Anticancer Research. 18(3A): 1479-84. ISSN: 0250-7005. May-June 1998.
12. El-Sherbiny YM, Cox MC, Ismail ZA, Shamsuddin AM and Vucenik I. G(0)/G(1) arrest and S phase inhibition of human cancer cell lines by inositol hexaphosphate (IP(6)). Anticancer Research. 21(4A): 2393-403. ISSN: 0250-7005. 2001.
13. Baten A, Ullah A, Tomazic VJ and Shamsuddin AM. Inositol-phosphate-induced enhancement of natural killer cell activity correlates with tumor suppression. Carcinogenesis. 10(9): 1595-98. ISSN: 0143-3334. Sep 1989.
14. Gearin-Tosh Michael. Living Proof. Scribner. ISBN 0-7432-0677-0. 2002.

Bibliography

Greaves Mel. Cancer: the Evolutionary Legacy. Oxford University Press. ISBN 0-19-262835-6. 2000.
Wade Nicholas. Life Script, the Genome and New Medicine. Simon & Schuster. ISBN 0-7432-0697-5. 2001.

Useful Web Addresses

IP6 information: www.AboutIP6.com and www.IP-6.net
Cancer Research UK: www.cancerresearchuk.org
Cancer statistics: www.doh.gov.uk/index.html
The National Cancer Institute: www.nci.nih.gov
Patient support: www.cancerlink.org

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About Marcus Webb,

Marcus Webb BSc, ND, MIBiol, CBiol is a registered osteopath and naturopath. He qualified in 1988 after which he taught osteopathic techniques and clinical methods for four years while his own practice became established in North London. During his professional life, Marcus became actively involved in writing for health magazines calling upon his experience and interest in integrative methods. Following an in-depth study of osteoporosis and his postgraduate studies at the University of Derby, the Institute of Biology granted Marcus Chartered status, a respected award in the bioscience industry. Marcus became involved with the research work of Dr Shamsuddin in 1997 and has helped to develop the role of inositol hexaphosphate (IP6) in cancer care since. He currently lives with his wife and three children in North London and is studying part-time for his MSc in Molecular Biology at King's College London. He can be contacted on Tel: 020 8441-8352; marcus.webb@btinternet.com

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