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      Molecular targets of pomegranate ( Punica granatum) in preventing cancer metastasis

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          Abstract

          Metastasis is the primary cause of mortality and morbidity among cancer patients and accounts for about 90% of cancer deaths. The most common types of treatment for cancer metastasis are chemotherapy and radiotherapy. However, such therapy has many serious side effects that could diminish the quality of life in patients. There is increased appreciation by the scientific community that natural compounds can be potential weapons in fighting against cancer. Interestingly, much evidence shows that pomegranate ( Punica granatum) has great potential to inhibit tumor growth and metastasis. In this review, we discussed the molecular targets of pomegranate, specifically, those that are prerequisite for cancer metastasis. The search was performed in Google Scholar, Medline, Scopus, and PubMed using keywords such as metastasis, pomegranate, and signaling pathways. Some of the most important papers from the search results were included. Based on recent studies, some molecules, including those involved in cell-cell and cell-extracellular matrix adhesions, are affected by pomegranate. The other targets of pomegranate are modulators of cytoskeleton dynamics and regulators of cancer cell anoikis and chemotaxis. Furthermore, the antimetastatic effect of pomegranate may be attributed to molecular changes of the extracellular matrix. Pro-inflammatory and pro-angiogenic molecules are the other targets of pomegranate regarding cancer metastasis. A wide variety of molecules can be targeted by pomegranate to suppress tumor metastasis. A better understanding of the molecules regulated by pomegranate is needed to provide a rational basis for its clinical application.

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          Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing.

          The antioxidant activity of pomegranate juices was evaluated by four different methods (ABTS, DPPH, DMPD, and FRAP) and compared to those of red wine and a green tea infusion. Commercial pomegranate juices showed an antioxidant activity (18-20 TEAC) three times higher than those of red wine and green tea (6-8 TEAC). The activity was higher in commercial juices extracted from whole pomegranates than in experimental juices obtained from the arils only (12-14 TEAC). HPLC-DAD and HPLC-MS analyses of the juices revealed that commercial juices contained the pomegranate tannin punicalagin (1500-1900 mg/L) while only traces of this compound were detected in the experimental juice obtained from arils in the laboratory. This shows that pomegranate industrial processing extracts some of the hydrolyzable tannins present in the fruit rind. This could account for the higher antioxidant activity of commercial juices compared to the experimental ones. In addition, anthocyanins, ellagic acid derivatives, and hydrolyzable tannins were detected and quantified in the pomegranate juices.
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            Cancer metastases: challenges and opportunities

            Cancer metastasis is the major cause of cancer morbidity and mortality, and accounts for about 90% of cancer deaths. Although cancer survival rate has been significantly improved over the years, the improvement is primarily due to early diagnosis and cancer growth inhibition. Limited progress has been made in the treatment of cancer metastasis due to various factors. Current treatments for cancer metastasis are mainly chemotherapy and radiotherapy, though the new generation anti-cancer drugs (predominantly neutralizing antibodies for growth factors and small molecule kinase inhibitors) do have the effects on cancer metastasis in addition to their effects on cancer growth. Cancer metastasis begins with detachment of metastatic cells from the primary tumor, travel of the cells to different sites through blood/lymphatic vessels, settlement and growth of the cells at a distal site. During the process, metastatic cells go through detachment, migration, invasion and adhesion. These four essential, metastatic steps are inter-related and affected by multi-biochemical events and parameters. Additionally, it is known that tumor microenvironment (such as extracellular matrix structure, growth factors, chemokines, matrix metalloproteinases) plays a significant role in cancer metastasis. The biochemical events and parameters involved in the metastatic process and tumor microenvironment have been targeted or can be potential targets for metastasis prevention and inhibition. This review provides an overview of these metastasis essential steps, related biochemical factors, and targets for intervention.
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              Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion.

              Cells adhere to one another and/or to matrices that surround them. Regulation of cell-cell (intercellular) and cell-matrix adhesion is tightly controlled in normal cells, however, defects in cell adhesion are common in the majority of human cancers. Multilateral communication among tumor cells with the extracellular matrix (ECM) and neighbor cells is accomplished through adhesion molecules, ECM components, proteolytic enzymes and their endogenous inhibitors. There is sufficient evidence to suggest that reduced adherence is a tumor cell property engaged during tumor progression. Tumor cells acquire the ability to change shape, detach and easily move through spaces disorganizing the normal tissue architecture. This property is due to changes in expression levels of adhesion molecules and/or due to elevated levels of secreted proteolytic enzymes, including matrix metalloproteinases (MMPs). Among other roles, MMPs degrade the ECM and, therefore, prepare the path for tumor cells to migrate, invade and spread to distant secondary areas, where they form metastasis. Tissue inhibitors of metalloproteinases or TIMPs control MMP activities and, therefore, minimize matrix degradation. Both MMPs and TIMPs are involved in tissue remodeling and decisively regulate tumor cell progression including tumor angiogenesis. In this review, we describe and discuss data that support the important role of MMPs and TIMPs in cancer cell adhesion and tumor progression. Published by Elsevier Ltd.
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                Author and article information

                Journal
                Iran J Basic Med Sci
                Iran J Basic Med Sci
                ijbms
                Iranian Journal of Basic Medical Sciences
                Mashhad University of Medical Sciences (Mashhad, Iran )
                2008-3866
                2008-3874
                September 2019
                : 22
                : 9
                : 977-988
                Affiliations
                [1 ]Cancer Prevention Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
                Author notes
                [* ]Corresponding author: Naghmeh Ahmadiankia. Cancer Prevention Research Center, Shahroud University of Medical Sciences, 7 tir square, Shahroud, Iran. Tel/Fax: +98-2332395054; +98-2332394800; Email: Ahmadian@shmu.ac.ir
                Article
                10.22038/ijbms.2019.34653.8217
                6880535
                31807240
                8c349daa-9878-4208-82e2-867d920513b1

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 4 September 2018
                : 14 May 2019
                Categories
                Review Article

                anoikis,cell adhesion,chemotaxis,cytoskeleton dynamics,extracellular matrix,metastasis,phytochemicals pomegranate

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