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Inositol and its phosphorylated form - inositol hexaphosphate (IP6) are naturally occurring carbohydrates, abundantly found in certain high-fiber diets, such as cereals and legumes. They, as well as other inositol phosphates with fewer phosphate groups (IP1-5) are contained in almost all mammalian cells, although in much smaller amounts, where they are important in regulating vital cellular functions. A striking anticancer action of IP6 was demonstrated in different experimental models. Although inositol possesses a modest anticancer activity, the most consistent and best anticancer results were obtained from the combination of Inositol IP6. In addition to reducing cell proliferation, IP6 increases differentiation of malignant cells, often resulting in reversion to normal phenotype with decreasing production of tumor markers such as CEA, PSAP, and AFP. Exogenously administered IP6 is rapidly taken into the cells and dephosphorylated to lower inositol phosphates, which further affect signal transduction pathways resulting in cell cycle arrest. Enhanced immunity and antioxidant properties also contribute to tumor cell destruction. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, Inositol IP6 holds great promise in our strategies for both prevention and therapy of cancer. Inositol IP6 enhances the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves the quality of life, as shown in pilot clinical studies. Emerging clinical and rather vast amount of laboratory data accumulated so far strongly suggest its role either as an adjuvant or as an "alternative" to current chemotherapy for cancer. In addition to cancer, Inositol IP6 has great potential in prevention of kidney stones, diabetic complications and atherosclerotic cardiovascular diseases, ailments that afflict people throughout the world.

Inositol and its phosphorylated form - inositol hexaphosphate (IP6) are naturally occurring carbohydrates, abundantly found in certain high-fiber diets, such as cereals and legumes. They, as well as other inositol phosphates with fewer phosphate groups (IP1-5) are contained in almost all mammalian cells, although in much smaller amounts, where they are important in regulating vital cellular functions. A striking anticancer action of IP6 was demonstrated in different experimental models. Although inositol possesses a modest anticancer activity, the most consistent and best anticancer results were obtained from the combination of Inositol + IP6. In addition to reducing cell proliferation, IP6 increases differentiation of malignant cells, often resulting in reversion to normal phenotype with decreasing production of tumor markers such as CEA, PSAP, and AFP. Exogenously administered IP6 is rapidly taken into the cells and dephosphorylated to lower inositol phosphates, which further affect signal transduction pathways resulting in cell cycle arrest. Enhanced immunity and antioxidant properties also contribute to tumor cell destruction. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, Inositol + IP6 holds great promise in our strategies for both prevention and therapy of cancer. Inositol + IP6 enhances the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves the quality of life, as shown in pilot clinical studies. Emerging clinical and rather vast amount of laboratory data accumulated so far strongly suggest its role either as an adjuvant or as an "alternative" to current chemotherapy for cancer. In addition to cancer, Inositol + IP6 has great potential in prevention of kidney stones, diabetic complications and atherosclerotic cardiovascular diseases, ailments that afflict people throughout the world.

Summary: Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate with demonstrated anti-proliferative and anti-cancer activity in mammary cells. We hypothesized that IP6 modulates cell cycle proteins by action on cytoplasmic signaling molecules. The effects of both pharmacological (2 mM) and physiological (100 mgrM) doses of IP6 on major PKC isoforms (PKCagr, delta, epsi, beta and zeta), PI3-K/Akt and ras/Erk1/2 were evaluated. Treatment of MCF-7 human breast cancer cells with 2 mM IP6 for 24 h caused a 3.1-fold increase in the expression of anti-proliferative PKCdelta. Similar results were observed with 100 mgrM IP6 at only 30–60 min post-treatment. IP6 also caused an increase in PKCdelta activity, shown by its translocation from cytosol to membrane. No changes in expression of PKC agr, delta, epsi, beta and zeta were detected. Additionally, IP6 caused a decrease of Erk1/2 and Akt activity. Among cell cycle control proteins, IP6 resulted in increased p27Kip1 protein levels and marked reduction of pRb phosphorylation. Specificity of the IP6 effects on p27Kip1 and pRb in MCF-7 cells (hormone-dependent) were additionally confirmed in highly invasive hormone-independent MDA-MB 231 breast cancer cells. Use of specific pharmaclogical inhibitors of PKC delta, MEK/Erk, and PI3K/Akt pathways indicated that the IP6-mediated effects on PKC delta were responsible for up-regulation of p27Kip, and pRb hypo-phosphorylation. In addition, IP6-induced apoptosis detected in MCF-7 cells appeared also to be PKC delta-dependent. Our data suggest potential usefulness of IP6 as a novel therapeutic modulator of PKC delta and p27Kip1, an important prognostic factor in human breast cancers.

A significant anticancer activity of the naturally occurring carbohydrate inositol hexaphosphate (IP6) has been reported against numerous cancer models. Since tumors require angiogenesis for growth and metastasis, we hypothesize that IP6 reduces tumor growth by inhibiting angiogenesis. Because angiogenesis depends on the interaction between endothelial and tumor cells, we investigated the effect of IP6 on both. IP6 inhibited the proliferation and induced the differentiation of endothelial cells in vitro; the growth of bovine aortic endothelial cells (BAECs) evaluated by MTT proliferation assay was inhibited in a dose-dependent manner (IC50 = 0.74 mM). The combination of IP6 and vasostatin, a calreticulin fragment with anti-angiogenic activity, was synergistically superior in growth inhibition than either compound. IP6 inhibited human umbilical vein endothelial cell (HUVEC) tube formation (in vitro capillary differentiation) on a reconstituted extracellular matrix, Matrigel, and disrupted pre-formed tubes. IP6 significantly reduced basic fibroblast growth factor (bFGF)-induced vessel formation (P < 0.01) in vivo in Matrigel plug assay. Exposure of HepG2, a human hepatoma cell line, to IP6 for 8 h, resulted in a dose-dependent decrease in the mRNA levels of vascular endothelial growth factor (VEGF), as assessed by RT–PCR. IP6 treatment of HepG2 cells for 24 h also significantly reduced the VEGF protein levels in conditioned medium, in a concentration-dependent manner (P = 0.012). Thus, IP6 has an inhibitory effect on induced angiogenesis.

The current treatment of breast carcinomas recognizes the importance of combination therapy in order to increase efficacy and decrease side effects of conventional chemotherapy. Inositol hexaphosphate (IP6), a naturally occurring polyphosphorylated carbohydrate, has shown a significant anti-cancer effect in various in vivoand in vitromodels, including breast cancer. In this study, we investigated the in vitrogrowth inhibitory activity of IP6in combination with adriamycin or tamoxifen, against three human breast cancer cell lines: estrogen receptor (ER)α-positive MCF-7, ERα-negative MDA-MB 231 and adriamycin-resistant MCF-7 (MCF-7/Adr) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Much lower concentrations of IP6were required after 96 h of treatment to inhibit the growth of MCF-7/Adr cells than MCF-7 cells; the IC50for MCF-7/Adr cells was 1.26 mM compared to 4.18 mM for MCF-7 cells. The ER-negative MDA-MB 231 cells were also highly sensitive to IP6with IC50being 1.32 mM. To determine the effects of IP6in combination with either adriamycin or tamoxifen, the median effect principle and Webb's fraction method were used to determine the combination index (CI) and the statistical differences. Growth suppression was markedly increased when IP6was administered prior to the addition of adriamycin, especially against MCF-7 cells (CI = 0.175 and p< 0.0001). Synergism was also observed when IP6was administered after tamoxifen in all three cell lines studied (CI = 0.343, 0.701 and 0.819; p> 0.0001, p= 0.0003 and 0.0241 for MCF-7/Adr, MCF-7 and MDA-MB 231, respectively). The growth of primary culture of breast cancer cells from patients was inhibited by IP6with LC50values ranging from 0.91 to 5.75 mM (n= 10). Our data not only confirm that IP6alone inhibits the growth of breast cancer cells; but it also acts synergistically with adriamycin or tamoxifen, being particularly effective against ERα-negative cells and adriamycin-resistant cell lines.

AbstractInositol hexaphosphate (IP6), abundant in cereals and legumes, has been demonstrated to be a promising an‐ticancer agent in differentin vivo andin vitro models. Because IP6 is particularly abundant in the bran part of certain mature seeds such as wheat, we investigated whether a high‐fiber bran diet containing high IP6 shows a dose‐response inhibition of 7,12‐dimethylbenz[a]anthracene (DMBA)‐in‐duced rat mammary carcinogenesis. Starting at two weeks before DMBA intubation, rats were divided into five groups and fed AIN‐76A diet only or AIN‐76A diet containing 5%, 10%, or 20% Kelloggs’ All Bran; the fifth group received 0.4% IP6 given in drinking water, an amount equivalent to the IP6 content in 20% bran. After carcinogen administration, the rats remained on these regimens for 29 weeks. Compared with the carcinogen control, at 29th week, tumor incidence was reduced by 16.7%, 14.6%, and 11.4% in rats fed 5%, 10%, and 20% bran, respectively (not statistically significant). However, rats given 0.4% IP6 in drinking water, equivalent to that in 20% bran, had a 33.5% reduction in tumor incidence (p < 0.02) and 48.8% fewer tumors (p < 0.03). These data show that supplemental dietary fiber in the form of bran exhibited a very modest, statistically nonsignificant inhibitory effect, which was also not dose dependent. In contrast, animals given IP6 showed significant reduction in tumor number, incidence, and multiplicity. Thus IP6, an active substance responsible for cereal's beneficial anti‐cancer effect, is clearly more effective than 20% bran in the diet. In practical terms, intake of IP6 may be a more pragmatic approach than gorging enormous quantities of fiber for cancer prophylaxis.

Wistaria floribunda agglutinin (WFA), Sophora japonica agglutinin (SJA) and Maclura pomifera lectin (MPL) were employed as immunofluorescent and leucoagglutinating reagents to study murine lymphocytes. WFA, which labels 90% of thymocytes, binds to only 57% of the splenocyte population. The latter subset corresponds to surface immunoglobulin bearing cells. Differential agglutination of splenocytes with this lectin results in the isolation of a WFA negative population which exhibits T-lymphocyte surface markers. The agglutinable splenocytes bind only 2.5 times more WPA than non-agglutinable cells suggesting that the preferential agglutination of B-splenocytes is due to a combination of reduced cell surface negative charge and increased number of lectin binding sites on these cells as compared to T-lymphocytes. Forty percent of splenocytes are positive for SJA and differential agglutination of splenocytes yields a population of SJA non-agglutinable cells that are not labeled by this lectin. The two populations fractionated by SJA are unrelated to T- and B-lymphocyte subsets. Differential agglutination of thymocytes by SJA yields a non-agglutinable group representing 42% of total thymocytes. Although the nature of the two thymocyte subsets discriminated by SJA remains unknown, this lectin appears useful in identifying and separating unique thymocyte and splenocyte populations.

To understand the mechanism of antineoplastic action of phytic acid, we investigated the absorption and distribution of myo-[inositol-2-3H(N)]hexakisphosphate in rats. The radioactivity was measured in urine, feces, blood, gastrointestinal tract contents and various organs and tissues at 1 and 24 h after intragastric administration. Of the total radioactivity, 79.0 ± 10.0% was absorbed and at least 26.6% was degraded during the 24-h period following ingestion. The absorption was rapid; 11.0 ± 2.6% of the radioactivity was detected in the wall of the stomach (4.4 ± 3.7%) and upper small intestine (6.6 ± 1.9%), 6.5 ± 2.6% in the skeletal muscle and 4.0 ± 1.5% in the skin after 1 h. Much of the radioactivity after 24 h was in the liver (4.0 ± 0.9%), kidneys (2.2 ± 1.1%), muscle (18.1 ± 3.4%) and skin (10.1 ± 3.3%). Analysis of plasma and urine demonstrated that most of the radioactivity was due to myo-inositol and small amounts of inositol monophosphate (InsP1). Gastric epithelial cells, however, contained inositol and various inositol phosphates (InsP1–6). Our data suggest that soluble InsP6when administered in drinking water is rapidly absorbed through the stomach and upper small intestine, becomes quickly dephosphorylated within the mucosal cells and is distributed to various organs as inositol and InsP1.