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Abstract: Inositol hexaphosphate (IP6) is effective in preclinical cancer prevention and chemotherapy. In addition to cancer, IP6 has many other beneficial effects for human health, such as reduction in risk of developing cardiovascular disease and diabetes and inhibition of kidney stone formation. Studies presented here describe the pharmacokinetics, tissue distribution, and metabolism of IP6 following intravenous (IV) or per os (PO) administration to mice. SCID mice bearing MDA-MB-231 xenografts were treated with 20 mg/kg IP6 (3 μCi per mouse [14C]-uniformly ring-labeled IP6) and euthanized at various times after IP6 treatment. Plasma and tissues were analyzed for [14C]-IP6 and metabolites by high-performance liquid chromatography with radioactivity detection. Following IV administration of IP6, plasma IP6 concentrations peaked at 5 minutes and were detectable until 45 minutes. Liver IP6 concentrations were more than 10-fold higher than plasma concentrations, whereas other normal tissue concentrations were similar to plasma. Only inositol was detected in xenografts. After PO administration, IP6 was detected in liver; but only inositol was detectable in other tissues. After both IV and PO administration, exogenous IP6 was rapidly dephosphorylated to inositol; however, alterations in endogenous IPs were not examined. [Copyright &y& Elsevier]

Chrysaora quinquecirrha (sea nettle) nematocyst venom is lethal to rainbow killifish (Adina xenica) when injected intraperitoneally or topically applied to the exposed brain or denuded epithelium. The lethal activity is thermostable requiring 100°C heat for inactivation. This paper reports here for the first time that the venom also activates the complement system with the subsequent formation of the C5b-9 terminal complement complex. The events are associated with both a strong chemoattractant release and the tissue damage. These are also, at least in part, responsible for the pathogenesis of some clinical signs and symptoms associated to the jellyfish stings. [Copyright &y& Elsevier]

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 IP[sub 6] 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 IP[sub 6] plus inositol. In addition to reducing cell proliferation, IP[sub 6] increases differentiation of malignant cells, often resulting in a reversion to normal phenotype. Exogenously administered IP[sub 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 in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, IP[sub 6] holds great promise in our strategies for the prevention and treatment of cancer. IP[sub 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 use of IP[sub 6] plus inositol in our strategies for cancer prevention and treatment. However, the effectiveness and safety of IP[sub 6] plus inositol at therapeutic doses needs to be determined in phase I and phase II clinical trials in humans. [ABSTRACT FROM AUTHOR]

The article focuses on the 2006 annual International Research Conference on Food, Nutrition, and Cancer sponsored by the American Institute for Cancer Research/World Cancer Research Fund International (AICR/WCRF) in Washington D.C. The conference was attended by nearly 400 people, which was opened by Kathryn Ward, senior vice president of AICR. During the event, a video on the process behind the second Expert Report was shown with evidence linking food, nutrition, and physical activity to the risk of developing cancer.

InsP6 is abundant in cereals and legumes. InsP6 and lower inositol phosphates, in particular InsP3, participate in important intracellular processes. In addition, InsP6 possess significant health benefits, such as anti-cancer effect, kidney stones prevention, lowering serum cholesterol. Because of the insensitivity of existing methods for determination of non-radiolabeled inositol phosphates, little is known about the natural occurrence, much less on the concentrations of InsP6 and InsP3 in biological samples. Using gas chromatography-mass detection analysis of HPLC chromatographic fractions, we report a measurement of unlabeled total InsP3 and InsP6 (a) as they occur within cells culture, tissues, and plasma, and (b) their changes depending on the presence of exogenous InsP6. When rats were fed on a purified diet in which InsP6 was undetectable (AIN-76A) the levels of InsP6 in brain were 3.35 ± 0.57 (SE) μmol·kg−1 and in plasma 0.023 ± 0.008 (SE) μmol·l−1. The presence of InsP6 in diet dramatically influenced its levels in brain and in plasma. When rats were given an InsP6-sufficient diet (AIN-76A + 1% InsP6), the levels of InsP6 were about 100-fold higher in brain tissues (36.8 ± 1.8 (SE)) than in plasma (0.29 ± 0.02 (SE)); InsP6 concentrations were 8.5-fold higher than total InsP3 concentrations in either plasma (0.033 ± 0.012 (SE)) and brain (4.21 ± 0.55 (SE)). When animals were given an InsP6-poor diet (AIN-76A only), there was a 90% decrease in InsP6 content in both brain tissue and plasma (p < 0.001); however, there was no change in the level of total InsP3. In non-stimulated malignant cells (MDA-MB 231 and K562) the InsP6 contents were 16.2 ± 9.1 (SE) μmol·kg−1 for MDA-MB 231 cells and 15.6 ± 2.7 (SE) for K 562 cells. These values were around 3-fold higher than those of InsP3 (4.8 ± 0.5 μmol·kg−1 and 6.9 ± 0.1 (SE) for MDA-MB 231 and K562 cells respectively). Treatment of malignant cells with InsP6 resulted in a 2-fold increase in the intracellular concentrations of total InsP3 (9.5 ± 1.3 (SE) and 10.8 ± 1.0 (SE) μmol·kg−1 for MDA-MB 231 and K562 cells respectively, p < 0.05), without changes in InsP6 levels. These results indicate that exogenous InsP6 directly affects its physiological levels in plasma and brain of normal rats without changes on the total InsP3 levels. Although a similar fluctuation of InsP6 concentration was not seen in human malignant cell lines following InsP6 treatment, an increased intracellular levels of total InsP3 was clearly observed. [Copyright &y& Elsevier]

SIRT3 is a major mitochondrial deacetylase, which regulates various metabolic pathways by deacetylation; however, the effect of SIRT3 on proline metabolism is not reported. Pyrroline-5-carboxylate reductase 1 (PYCR1) participates in proline synthesis process by catalyzing the reduction of P5C to proline with concomitant generation of NAD+ and NADP+. PYCR1 is highly expressed in various cancers, and it can promote the growth of tumor cells. Here, through immunoprecipitation and mass spectrometry, we found that PYCR1 is in SIRT3's interacting network. PYCR1 directly binds to SIRT3 both in vivo and in vitro. CBP is the acetyltransferase for PYCR1, whereas SIRT3 deacetylates PYCR1. We further identified that K228 is the major acetylation site for PYCR1. Acetylation of PYCR1 at K228 reduced its enzymatic activity by impairing the formation of the decamer of PYCR1. As a result, acetylation of PYCR1 at K228 inhibits cell proliferation, while deacetylation of PYCR1 mediated by SIRT3 increases PYCR1's activity. Our findings on the regulation of PYCR1 linked proline metabolism with SIRT3, CBP and cell growth, thus providing a potential approach for cancer therapy. [ABSTRACT FROM AUTHOR]