Abulkalam M. Shamsuddin

Cancer Inhibition by Inositol Hexaphosphate (IP6) and Inositol: From Laboratory to Clinic

Inositol hexaphosphate (IP6) 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 IP6 was demonstrated in different experimental models. Inositol is also a natural constituent possessing moderate anticancer activity. The most consistent and best anticancer results were obtained from the combination of IP6 plus inositol. In addition to reducing cell proliferation, IP6 increases differentiation of malignant cells, often resulting in a reversion to normal phenotype. Exogenously administered IP6 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 in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP6 holds great promise in our strategies for the prevention and treatment of cancer. IP6 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 use of IP6 plus inositol in our strategies for cancer prevention and treatment. However, the effectiveness and safety of IP6 plus inositol at therapeutic doses needs to be determined in phase I and phase II clinical trials in humans.

Protection Against Cancer by Dietary IP6 and Inositol

Abstract: Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate, abundantly present in many plant sources and in certain high-fiber diets, such as cereals and legumes. In addition to being found in plants, IP6 is contained in almost all mammalian cells, although in much smaller amounts, where it is important in regulating vital cellular functions such as signal transduction, cell proliferation, and differentiation. For a long time IP6 has been recognized as a natural antioxidant. Recently IP6 has received much attention for its role in cancer prevention and control of experimental tumor growth, progression, and metastasis. In addition, IP6 possesses other significant benefits for human health, such as the ability to enhance immune system, prevent pathological calcification and kidney stone formation, lower elevated serum cholesterol, and reduce pathological platelet activity. In this review we show the efficacy and discuss some of the molecular mechanisms that govern the action of this dietary agent. Exogenously administered IP6 is rapidly taken up into cells and dephosphorylated to lower inositol phosphates, which further affect signal transduction pathways resulting in cell cycle arrest. A striking anticancer action of IP6 was demonstrated in different experimental models. In addition to reducing cell proliferation, IP6 also induces differentiation of malignant cells. Enhanced immunity and antioxidant properties also contribute to tumor cell destruction. Preliminary studies in humans show that IP6 and inositol, the precursor molecule of IP6, appear to enhance the anticancer effect of conventional chemotherapy, control cancer metastases, and improve quality of life. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP6 + inositol holds great promise in our strategies for cancer prevention and therapy. There is clearly enough evidence to justify the initiation of full-scale clinical trials in humans.

IP6 : A NOVEL ANTI-CANCER AGENT

Inositol hexaphosphate (InsP6 or IP6) is ubiquitous. At 10 microM to 1 mM concentrations, IP6 and its lower phosphorylated forms (IP(1-5)) as well as inositol (Ins) are contained in most mammalian cells, wherein they are important in regulating vital cellular functions such as signal transduction, cell proliferation and differentiation. A striking anti-cancer action of IP6 has been demonstrated both in vivo and in vitro, which is based on the hypotheses that exogenously administered IP6 may be internalized, dephosphorylated to IP(1-5), and inhibit cell growth. There is additional evidence that Ins alone may further enhance the anti-cancer effect of IP6. Besides decreasing cellular proliferation, IP6 also causes differentiation of malignant cells often resulting in a reversion to normal phenotype. These data strongly point towards the involvement of signal transduction pathways, cell cycle regulatory genes, differentiation genes, oncogenes and perhaps, tumor suppressor genes in bringing about the observed anti-neoplastic action of IP6.

Inositol phosphates have novel anticancer function

Inositol hexaphosphate (InsP6, phytic acid) is ubiquitous in the plant kingdom and is abundant in cereals and legumes. In much smaller amounts InsP6 and its lower phosphorylated forms (InsP1-5) are contained in most mammalian cells, where they are important in regulating vital cellular functions. Both in vivo and in vitro experiments have suggested striking anticancer potential (preventive as well as therapeutic) for InsP6 with and without inositol. In addition to reduce cell proliferation, InsP6 increases differentiation of malignant cells often resulting in reversion to the normal phenotype. InsP6 is quickly absorbed from the rat stomach and upper intestine and distributed as inositol and InsP1. In vitro it is instantaneously taken up by malignant cells undergoing variable dephosphorylation to inositol and InsP1-5, pointing toward their role in mediating the action of InsP6. Because InsP6 is high in high-fiber diets, our studies also may explain, at least in part, the epidemiologic observation showing high-fiber diets are associated with a lower incidence of certain cancers. Although further studies are needed to elucidate the mechanism(s) of this action, inclusion of InsP6 in our strategies for cancer prevention and therapy is warranted.

Human large intestinal epithelium: Light microscopy, histochemistry, and ultrastructure*

Despite numerous reports of morphologic characteristics of premalignant and malignant large intestinal epithelium, the literature lacks comprehensive reports of the morphologic features of the epithelium of the normal large intestine, except of the rectum. Large intestinal epithelium from 41 persons was obtained, and samples from the ascending, transverse, descending, and rectosigmoid areas were studied by light microscopy, histochemical techniques, and transmission and scanning electron microscopy. The morphologic features and histochemical reactions of the various segments of the large intestine are different. Neutral mucopolysaccharide is predominant in the ascending colon, whereas the rectum has predominantly or exclusively acidic mucin. Only three basic epithelial cell phenotypes have been identified: undifferentiated cells, mucous cells, and endocrine cells. The columnar cells at the surface between the crypts appear to be a variant of mucous cells. Compared with other segments, the rectum shows an unusually high concentration of endocrine cells, positively correlating with the high incidence of carcinoid tumors in that segment of the large intestine. The mucous cells in all segments contain large mucous vacuoles and small apical vesicles. The apical vesicles show variable electron density, being most dense in the ascending colon and becoming progressively less dense at the transverse and descending colon and most electron-lucent in the sigmoid colon and rectum. Ultrastructurally, the mucin shows a variable degree of heterogeneity in the proximal segments. This study suggests that some of the previously described ultrastructural features of abnormal large-intestinal epithelium may be only the result of failure to compare the so-called abnormal cells with normal cells from the same region. Well-controlled studies of the abnormal epithelium of a particular segment of large intestine must include the normal epithelium from the identical segment as control in order to make interpretations accurate.

Effects of inositol hexaphosphate on growth and differentiation in K-562 erythroleukemia cell line

Inositol hexaphosphate (InsP6) has recently been shown to inhibit experimental cancers in vivo. Since the lower phosphorylated forms of InsP6 are important in cell growth in a wide variety of mammalian cells, we tested the efficacy of InsP6 in growth reduction of K-562 human erythroleukemia cells in vitro. We report that InsP6 decreases the K-562 cell population by 19-36% (P less than 0.001) concomitant to an increased differentiation as evidenced by ultrastructural morphology and increased hemoglobin synthesis. Pilot experiments to study the mechanism of action of InsP6 show that following treatment with InsP6, the concentration of intracellular [Ca2+] ([Ca2+]i) is increased by 57% (P less than 0.02). Likewise, a 41% increase (P less than 0.05) in InsP3 and a 26% decrease (P less than 0.02) in InsP2 were noted 1 h following treatment with InsP6. Contrary to the dogma that cell division is associated with increased [Ca2+]i, our data show that reduced cell growth and enhanced differentiation is associated with increased [Ca2+]i and increased InsP3 in the presence of InsP6.

Antitumor activity of phytic acid (inositol hexaphosphate) in murine transplanted and metastatic fibrosarcoma, a pilot study

We have previously reported that phytic acid (inositol hexaphosphate or InsP6), a natural constituent of cereal diet, when administered in drinking water exerts a consistent antitumor effect on experimental colon cancer in vivo. The objective of this study was to determine whether InsP6 has similar anti-neoplastic effect on other tumor models, such as murine fibrosarcoma. We report that intraperitoneal injection of InsP6 reduces growth of subcutaneously transplanted fibrosarcoma (FSA-1) in mice, prolongs survival of tumor-bearing mice and reduces the number of pulmonary metastases. Since InsP6 is a common constituent of our diet and has very little or no toxic effects, in addition to being chemopreventive, it could have potential use in therapy of cancer as well.

The effects of leukemic infiltrates in various organs in chronic lymphocytic leukemia

Abstract Although the presence of leukemic infiltrate in isolated organs of patients with chronic lymphocytic leukemia has been reported, the effects of leukemic infiltration into various organs of such patients have never been comprehensively studied. To determine the effects of leukemic infiltration we reviewed the histologic sections of multiple organs in 47 cases of chronic lymphocytic leukemia at the University of Maryland Hospital. The leukemic infiltrates were seen in spleen (100 per cent), lymph nodes (100 per cent), liver (98 per cent), kidney (90 per cent), adrenal (71 per cent), heart (64 per cent), and pancreas (37 per cent). After exclusion of the known causes of fibrosis in these organs, the association of fibrosis with leukemic infiltration was as follows: liver (44 per cent), kidney (89 per cent), heart (44 per cent), pancreas (60 per cent), and adrenal (3 per cent). The heart showed endocardial, myocardial, and epicardial infiltrates associated with fibrosis, with severe endocardial fibroelastosis in one case. The liver showed expansion of the portal tracts, bridging infiltration, bridging fibrosis, and cirrhosis with pseudolobule formation. In patients whose livers showed bridging fibrosis or pseudolobule formation, the mean duration of chronic lymphocytic leukemia was 4,4 years, compared to 2.6 years in those showing no significant fibrosis, suggesting that the degree of infiltration and fibrosis was positively correlated with the duration of leukemia. The kidney showed interstitial and periglomerular fibrosis and tubular atrophy only in areas of leukemic infiltration, whereas no fibrosis or atrophy was observed in noninfiltrated areas. The renal lesions closely resembled the chronic inflammatory conditions of the kidney. In foci of leukemic infiltration the pancreas showed parenchymal destruction and fibrous scars, thereby resembling chronic pancreatitis. The adrenals showed replacement of medullary cells by dense leukemic infiltrates, and fibrosis was observed in one case. A strong association between fibrosis and the lymphocytic infiltration of chronic lymphocytic leukemia in various organs has been demonstrated. We therefore suggest that chronic lymphocytic leukemia may cause significant tissue destruction. Further studies are needed in this area.

Carcinoma in situ in nonpolypoid mucosa of the large intestine report of a case with significance in strategies for early detection

A case of carcinoma in situ of the flat, nonpolypoid mucosa of the large intestine in a 32‐year‐old man is reported. This case is of unusual importance because (1) it was detected by endoscopy and was effectively managed; (2) it sheds further light into the histogenesis of large intestinal carcinomas; and (3) it points to alternate strategies for early detection and prevention of large intestinal carcinomas.

Explant culture of rat colon: A model system for studying metabolism of chemical carcinogens

SummaryAn explant culture system has been developed for the long-term maintenance of colonic tissue from the rat. Explants of 1 cm2 in size were placed in tissue-culture dishes to which was added 2 ml of CMRL-1066 medium supplemented with glucose, hydrocortisone, β-retinyl acetate, and either 2.5% bovine albumin or 5% fetal bovine serum. The dishes were placed in a controlied-atmosphere chamber which was gassed with 95% O2 and 5% CO2. The chamber then was placed on a rocker platform which rocked at 10 cycles per min causing the medium to flow intermittently over the epithelial surface. The explants were incubated at 30°C. The viability of the tissue was measured both by incorporation of specific precursors into cellular macromolecules and by monitoring of tissue morphology with light and electron microscopy. Cultured rat colon was able to metabolize benzo[a]pyrene, 7,12-dimethylbenz[a]anthracene, aflatoxin B1, dimethylnitrosamine, 1,2-dimethylhydrazine, and methylazoxymethanol acetate into chemical species that bind to cellular DNA and protein.