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      Micronutrient synergy—a new tool in effective control of metastasis and other key mechanisms of cancer

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          Abstract

          Consumption of a plant-based diet has been associated with prevention of the development and progression of cancer. We have developed strategies to inhibit cancer development and its spread by targeting common mechanisms used by all types of cancer cells that decrease stability and integrity of connective tissue. Strengthening of collagen and connective tissue can be achieved naturally through the synergistic effects of selected nutrients, such as lysine, proline, ascorbic acid and green tea extract (NM). This micronutrient mixture has exhibited a potent anticancer activity in vivo and in vitro in a few dozen cancer cell lines. Its anti-cancer effects include inhibition of metastasis, tumor growth, matrix metalloproteinase (MMP) secretion, invasion, angiogenesis, and cell growth as well as induction of apoptosis. Many cancers are often diagnosed at later stages, when metastasis has occurred, which standard treatment has been unable to control. Our studies on NM effects on hepatic and pulmonary metastasis demonstrated profound, significant suppression of metastasis in a murine model. Evaluation of effects of NM on xenografts in murine models demonstrated significant reduction in tumor size and tumor burden in all human cancer cell lines tested. In vitro studies demonstrated that NM was very effective in inhibition of cell proliferation (by MTT assay), MMP secretion (by gelatinase zymography), cell invasion (through Matrigel), cell migration (by scratch test), induction of apoptosis (by live green caspase) and induction of pro-apoptotic genes in many diverse cancer cell lines. Furthermore, in vivo and in vitro studies of effects of individual micronutrients compared to their specific combination demonstrated synergistic effects resulting in improved anticancer potency.

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          Changing views of the role of matrix metalloproteinases in metastasis.

          Metastatic spread of cancer continues to be the greatest barrier to cancer cure. Understanding the molecular mechanisms of metastasis is crucial for the design and effective use of novel therapeutic strategies to combat metastases. One class of molecules that has been repeatedly implicated in metastasis is the matrix metalloproteinases (MMPs). In this review, we re-examine the evidence that MMPs are associated with metastasis and that they make a functional contribution to the process. Initially, it was believed that the major role of MMPs in metastasis was to facilitate the breakdown of physical barriers to metastasis, thus promoting invasion and entry into and out of blood or lymphatic vessels (intravasation, extravasation). However, recent evidence suggests that MMPs may have a more complex role in metastasis and that they may make important contributions at other steps in the metastatic process. Studies using intravital videomicroscopy, as well as experiments in which levels of MMPs or their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) are manipulated genetically or pharmacologically, suggest that MMPs are key regulators of growth of tumors, at both primary and metastatic sites. On the basis of this evidence, a new view of the functional role of MMPs in metastasis is presented, which suggests that MMPs are important in creating and maintaining an environment that supports the initiation and maintenance of growth of primary and metastatic tumors. Further clarification of the mechanisms by which MMPs regulate growth of primary and metastatic tumors will be important in the development of novel therapeutic strategies against metastases.
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            Nitric oxide synthase: role in the genesis of vascular disease.

            The product of nitric oxide (NO) synthase is the most potent endogenous vasodilator known. No not only is a potent vasodilator, it also inhibits platelet adherence and aggregation, reduces adherence of leukocytes to the endothelium, and suppresses proliferation of vascular smooth muscle cells. A number of disorders are associated with reduced synthesis and/or increased degradation of vascular NO. These include hypercholesterolemia, diabetes mellitus, hypertension, and tobacco use. The endothelial dysfunction caused by these disorders contributes to the alterations in vascular function and structure observed in these conditions. A reduction in the activity of vascular NO likely plays a significant role in the development of atherosclerosis. Insights into the mechanisms by which NO production or activity is altered in these states will lead to new therapeutic strategies in the treatment of a number of vascular disorders, including hypertension, atherosclerosis, restenosis, and thrombosis.
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              Inhibition of growth and induction of apoptosis in human cancer cell lines by tea polyphenols.

              In order to study the biological activities of tea preparations and purified tea polyphenols, their growth inhibitory effects were investigated using four human cancer cell lines. Growth inhibition was measured by [3H]thymidine incorporation after 48 h of treatment. The green tea catechins (-)-epigallocatechin-3-gallate (EGCG) and (-)-epigallocatechin (EGC) displayed strong growth inhibitory effects against lung tumor cell lines H661 and H1299, with estimated IC50 values of 22 microM, but were less effective against lung cancer cell line H441 and colon cancer cell line HT-29 with IC50 values 2- to 3-fold higher. (-)-Epicatechin-3-gallate, had lower activities, and (-)-epicatechin was even less effective. Preparations of green tea polyphenols and theaflavins had higher activities than extracts of green tea and decaffeinated green tea. The results suggest that the growth inhibitory activity of tea extracts is caused by the activities of different tea polyphenols. Exposure of H661 cells to 30 microM EGCG, EGC or theaflavins for 24 h led to the induction of apoptosis as determined by an annexin V apoptosis assay, showing apoptosis indices of 23, 26 and 8%, respectively; with 100 microM of these compounds, the apoptosis indices were 82, 76 and 78%, respectively. Incubation of H661 cells with EGCG also induced a dose-dependent formation of H2O2. Addition of H2O2 to H661 cells caused apoptosis in a manner similar to that caused by EGCG. The EGCG-induced apoptosis in H661 cells was completely inhibited by exogenously added catalase (50 units/ml). These results suggest that tea polyphenol-induced production of H2O2 may mediate apoptosis and that this may contribute to the growth inhibitory activities of tea polyphenols in vitro.
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                Author and article information

                Contributors
                author@drrath.com
                Journal
                Cancer Metastasis Rev
                Cancer Metastasis Reviews
                Springer US (Boston )
                0167-7659
                1573-7233
                18 August 2010
                18 August 2010
                September 2010
                : 29
                : 3
                : 529-542
                Affiliations
                Dr. Rath Research Institute, 1260 Memorex Drive, Santa Clara, CA 95050 USA
                Article
                9244
                10.1007/s10555-010-9244-1
                2933847
                20717705
                a450a290-805d-4032-b48b-917a6c90fea5
                © The Author(s) 2010
                History
                Categories
                Article
                Custom metadata
                © Springer Science+Business Media, LLC 2010

                Oncology & Radiotherapy
                tumor growth,synergy,metastasis,micronutrients,in vitro,in vivo
                Oncology & Radiotherapy
                tumor growth, synergy, metastasis, micronutrients, in vitro, in vivo

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