ABSTRACT. Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that is present in substantial amounts in almost all plant and. Abstract: Inositol hexaphosphate (IP6) is a naturally occur- ring polyphosphorylated carbohydrate, abundantly present in many plant sources and in certain. While IP-6 is found in rice bran and other foods, there are good reasons to take an IP-6 & Inositol supplement. First, IP-6 is getter absorbed in pure form without.

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Ivana Vucenik, AbulKalam M. Inositol hexaphosphate IP 6 is a naturally occurring polyphosphorylated carbohydrate that is present in substantial amounts in almost all plant and mammalian cells. It was recently recognized to possess multiple biological functions.

A striking anticancer effect of IP 6 was demonstrated in different experimental models. Inpsitol is also a natural constituent possessing moderate anticancer activity. The most consistent and best anticancer results were obtained from the combination of IP 6 plus inositol. In addition to reducing cell proliferation, IP 6 increases differentiation of malignant cells, often resulting in a reversion to normal phenotype.

Exogenously administered IP 6 is rapidly taken into the cells and dephosphorylated to lower-phosphate inositol phosphates, which further interfere with signal transduction pathways and cell cycle arrest. Enhanced immunity and antioxidant properties can also contribute to tumor cell destruction. However, the molecular mechanisms underlying this anticancer action are not fully understood. Because it is abundantly present inosotol regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP 6 holds great promise in our strategies for the prevention and treatment of cancer.

IP 6 plus inositol enhances the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves the quality of life, as shown in a pilot clinical trial. The data strongly argue for the i6 of IP 6 plus inositol in our strategies inostol cancer prevention and treatment. However, the effectiveness and safety of Insitol 6 plus inositol at therapeutic doses needs to be determined in phase I and phase II clinical trials in humans. Cancer remains a major health problem in the United States and in other developed countries 1.

In our continuing effort to reduce the public health burden of cancer, there is a constant search for more effective cancer treatment, and increased interest inisitol the concept of prevention, as a promising approach to the control of cancer 2.

A novel anticancer function of inositol hexaphosphate IP 6 ; 4 also Ins P 6 and phytic acid has been shown both in vivo and in vitro 3 — 5. IP inosiotl is a polyphosphorylated carbohydrate, contained in high concentrations 0. Myo -inositol is a parent compound of IP 6. Only myo -inositol hexaphosphate has been found in plants; neo – chiro – and scyllo -inositol hexaphosphates have been isolated from soil 7.

The phosphate grouping in positions 1, 2, and 3 axial-equatorial-axial is unique for IP 6providing a specific interaction with iron to completely inhibit its ability to catalyze hydroxyl radical formation, making IP 6 a strong antioxidant, probably still the only role inosirol IP 6 that is widely recognized and accepted. Almost all mammalian cells contain IP 6 and much smaller amounts of its forms with fewer phosphate groups IPwhich are important for regulating vital cellular inosktol.

Cancer inhibition by inositol hexaphosphate (IP6) and inositol: from laboratory to clinic.

Inositol occurs ubiquitously in cell membranes in conjugation with lipids, as phosphatidylinositol. Recently, inositol phospholipids in the plasma membrane have received much attention because of their biological significance for signal transduction systems. It is now recognized that subsequent to PIP 2 hydrolysis a cascade of inositol phosphate metabolites are formed and that these multiple isomers show a complex pattern of interconversion 8 — Inositol phosphates are versatile molecules with important roles in controlling diverse cellular activities 9 IP 6 may serve as a natural antioxidant 11 and possibly as a neurotransmitter Different binding proteins for inositol polyphosphates have been isolated, indicating their importance for the cellular functions 12 such as effects on ion channels and protein trafficking 1314endocytosis 15exocytosis 16and efficient export of mRNA from the nucleus to the cell How can exogenously administered IP 6 affect tumor growth?

Pioneering experiments showing this novel anticancer feature of IP 6 were performed by Shamsuddin et al. Almost 15 y ago, Shamsuddin et al. It was also hypothesized that the addition of inositol, a precursor of inositol phosphates and also a natural carbohydrate, to IP 6 may enhance the anticancer function of IP 6 18 — Because inositol phosphates are common molecules involved in signal transduction in most mammalian cell systems, it was further hypothesized that the anticancer action of inositol phosphates would be observed in different cells and tissue systems 18 — All these proposed hypotheses have been confirmed.


Contrary to the dogma and skepticism at that time, we showed that IP 6 is taken up by malignant cells 21 and that orally administered IP 6 can reach target tumor tissue distant from the gastrointestinal tract Because of the highly charged nature of IP 6it was a common misconception that it could not be transported into the cells. Analyzing absorption, intracellular distribution, and metabolism of IP 6 in HT human colon carcinoma and cells of hematopoietic lineage K, human erythroleukemia and YAC-1, mouse lymphoma cellswe found that IP 6 is rapidly taken up by mechanisms probably involving pinocytosis or receptor-mediated endocytosis, transported intracellularly, and dephosphorylated into inositol phosphates with fewer phosphate groups When [ 3 H]-IP 6 was administered intragastrically to rats, it was quickly absorbed from the stomach and upper intestine and distributed to various organs as early as 1 h after administration Although the radioactivity isolated from gastric epithelium at this time was associated with inositol and IPthe radioactivity in the plasma and urine was associated with inositol and IP 1.

Protection against cancer by dietary IP6 and inositol.

These data indicate that the intact molecule was transported inside the gastric epithelial cells, wherein it was rapidly dephosphorylated, and that the metabolism of IP 6 was very rapid.

In our preliminary kp6, [ 3 H]-IP 6 was given via oral gavage to rats bearing 7,dimethylbenz[ inosifol ]anthracene-induced mammary tumors. A substantial amount of radioactivity These data indicate that IP 6 can reach and concentrate at cellular targets.

Chromatographic analysis of tumor tissue revealed inpsitol presence of inositol and IP 1jp6 to plasma. Using a novel and highly sensitive method combining gas chromatography—mass spectrometry analysis and HPLC, Grases et al. They also showed that the levels of IP 6 and its less phosphorylated forms fluctuate depending on the intake of IP 6.

That the extracellularly applied IP 6 enters the cell and that this intracellular delivery is followed by a dephosphorylation of IP 6 was recently confirmed by Ferry et al. As hypothesized, it was demonstrated that IP inositop is a broad-spectrum antineoplastic agent, affecting different cells and tissue systems. In vitro studies with IP inosigol are summarized in Table 1. IP 6 inhibited the growth of all tested cell lines in a dose- and time-dependent manner. The growth of cells of hematopoietic lineage was inhibited: The antiproliferative activity of IP 6 was further reported in human colon inosiotl HT cells 28estrogen receptor—positive and estrogen receptor—negative human breast cancer cells 32cervical cancer 25prostate cancer 153334and HepG2 hepatoma cell lines IP 6 also inhibited inositil growth of mesenchymal tumors, murine fibrosarcoma 39and human rhabdomyosarcoma However, cells from different origin have different sensitivity to IP 6 the leukemic cell lines seem to be highly susceptible to IP 6suggesting that IP 6 may affect different cell types through different mechanisms of action.

The potential of IP 6 to induce differentiation and maturation of malignant cells, often resulting in reversion to the normal phenotype, was first demonstrated in K hematopoietic cells IP 6 was further shown to increase differentiation of human colon carcinoma HT cells 2829prostate cancer cells 33breast cancer cells 32and rhabdomyosarcoma cells The observation that IP 6 impaired the transformation induced by epidermal growth factor or phorbol ester in JB6 mouse epidermal cells 35 strongly suggested the potential role of IP 6 as a cancer preventive agent, because this model has been a ihositol cell system for studying the tumor promotion i;6 molecular mechanisms of antitumor agents.

Furthermore, IP 6 reduced O -tetradecanoylphorbolacetate—induced ornithine decarboxylase activity, an essential event in tumor promotion in HEL cells, a murine keratinocyte cell line A summary of in vivo studies using IP 6 and inositol is shown in Table 2. Although experts in the field of nutrition and cancer have been performing in vivo experiments by adding IP 6 to the diet, in all our cancer prevention studies, IP 6 was given via drinking water in concentrations ranging from unositol.

We were able to obtain comparable or even stronger tumor inhibition with much lower concentrations of IP 6 when it was given in drinking water.

Protection against cancer by dietary IP6 and inositol.

For example, much stronger tumor inhibition was lnositol with 0. The effectiveness of IP 6 as a cancer preventive agent was shown in colon cancer induced in different species rats and mice with different carcinogens 12 -dimethylhydrazine and azoxymethane 18 — 2040 — IP inosiotl was effective in a dose-dependent inosiitol given either before or after carcinogen administration.

The finding that IP 6 was able to reduce the development of large intestinal cancer 5 mo after carcinogen administration, when IP 6 -treated animals demonstrated a significantly lower tumor number and size, has suggested its potential use as a therapeutic agent IP 6 decreased the incidence of aberrant crypts when they were used as an intermediate biomarker for colon cancer 43 Studies using other experimental models showed that antineoplastic properties of IP 6 were not restricted to the colon.


IP 6 significantly reduced experimental mammary carcinoma in Sprague-Dawley rats induced either by 7,dimethylbenz[ a ]anthracene 51 — 54 or N -methylnitrosourea Using a two-stage mouse skin carcinogenesis model, Ishikawa et al.

The therapeutic properties of IP 6 were demonstrated in the FSA-1 mouse model of transplantable and metastatic fibrosarcoma After imositol inoculation of mouse fibrosarcoma FSA-1 cells, mice were treated with intraperitoneal injections of IP 6 and a significant inhibition of tumor size and survival over untreated controls was observed. In this model experimental lung metastases are developed after intravenous injections of FSA-1 cells; intraperitoneal injections of IP 6 resulted in a significant reduction of metastatic lung colonies Inpsitol strong anticancer activity of IP 6 was also demonstrated against human rhabdomyosarcoma RD cells transplanted in nude mice 38where the efficacy of IP 6 was tested on the tumor-forming capacity iositol RD cells.

IP 6 was also potent in inhibiting experimental hepatoma 31 We tested the effect of IP 6 inostiol tumorigenicity and tumor regression in this model.

A single treatment of HepG2 cells in vitro by IP 6 resulted in the complete loss of the ability of these cells to form tumors when inoculated subcutaneously in nude onositol Additionally, the preexisting liver cancers regressed when they were treated directly with IP 6 Myo-inositol itself was also demonstrated to have anticancer function, albeit modest.

It inhibited pulmonary adenoma formation in mice 49 We found that inositol alone or in combination inosihol IP 6 can prevent the formation and incidence of several cancers in experimental animals: Additionally, we showed that inositol potentiates both the antiproliferative and antineoplastic effects of IP 6 in vivo 3 — 5193951 Synergistic cancer inhibition by IP 6 when combined with inositol was observed in colon cancer Table 3 19 and mammary cancer studies Table 4 51 Similar results were seen in the metastatic lung cancer model Thus, the combination of IP 6 and inositol was significantly better in different cancers than was either one alone.

Synergistic cancer inhibition by IP 6 when combined with inositol Ins 1,2-dimethylhydrazine Lnositol – induced colon carcinoma in mice. Adapted from Shamsuddin et al. The difference in total i6p of tumors, tumor burden No.

Cancer inhibition by inositol hexaphosphate (IP6) and inositol: from laboratory to clinic.

Adapted from Vucenik et al. The mechanisms involved in the anticancer activity of inositol compounds are not fully understood.

It is known that virtually all animal cells contain inositol phosphates and that the inositol lp6 with fewer phosphate groups, especially IP 3 and IP 4have an important role in cellular signal transduction, regulation of cell function, growth, and differentiation 89. We hypothesized that one of the several ways by which IP 6 plus inositol exerts its action is via lower-phosphate inositol phosphates.

Measurement of intracellular inositol phosphates after IP 6 treatment showed an increased level of lower-phosphate inositol phosphates IP 2124 — 26 ; their involvement in signal transduction pathways can affect cell cycle regulation, growth, and differentiation of malignant cells 3 — 5.

Derivatives of phosphatidylinositol transmit cellular signals in response to extracellular stimuli, and enzymes responsible for the phosphorylation and hydrolysis of these signaling lipids play an important role in a broad range of biological effects.

A central molecule is a phosphatidylinositol-3 kinase, which primarily phosphorylates the lipid phosphatidylinositol on the 3 position of the D- myo -inositol ring, yielding phosphatidylinositolphosphate, but also can use phosphorylated forms of phosphatidylinositol as substrates.

IP 6 inhibits phosphatidylinositol-3 kinase This action is related to the IP 6 structure that is similar to Ddeoxyfluoro-PtdIns, an inhibitor of phosphatidylinositol-3 kinase In addition to the blocking of phosphatidylinositol-3 kinase and activating protein-1 by IP 6 35protein kinase C 1657 and mitogen-activated protein kinases 1535 are involved in IP 6 -mediated anticancer activity.

The role of IP 6 among these multiple inosihol pathways and their cross-talk in regulation of cell functions needs to be addressed in the future. IP 6 can also modulate cellular response at the level of receptor binding.

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