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      2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione inhibits the growth and metastasis of breast carcinoma in mice

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          Abstract

          Metastasis causes approximately 90% of breast cancer-related deaths in women. Previously, we have demonstrated that 2-dodecyl-6-methoxycyclohexa-2,5-diene- 1,4-dione (DMDD) remarkably inhibited the growth of human breast cancer cells with little toxicity. In this study, we investigated the toxicity and efficacy of DMDD to treat metastatic breast tumors using an in vivo mouse model of the 4T1 mammary carcinoma. DMDD caused no observable toxicity and significantly extended the survival of 4T1 tumor-bearing mice. DMDD effectively inhibited the growth of 4T1 cells in vitro, and suppressed the growth and metastasis of mammary tumor in vivo. The levels of inflammatory cytokines in the serum (TNF-α, IL-6, IL-12, TGF-β, and VEGF) were down regulated by DMDD. Immunohistochemical analysis demonstrated that the inhibition of tumor growth and metastasis was associated with activation of Bax, cleaved caspases-3 and -9, and down-regulation of Bcl-2, MMP-2 and -9, NF-κB and IκBα. We speculate that DMDD inhibits cytokine production in the tumor cells in mice, which leads to deactivation of NF-κB pathway, and consequently inhibits the expression of many anti-apoptosis and metastasis-promoting genes, such as Bcl-2 and MMPs. Collectively, our results demonstrate the potential of DMDD as a safe and effective antitumor agent in the treatment of late-stage breast cancer.

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          Most cited references20

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          Tumor metastasis: molecular insights and evolving paradigms.

          Metastases represent the end products of a multistep cell-biological process termed the invasion-metastasis cascade, which involves dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to foreign tissue microenvironments. Each of these events is driven by the acquisition of genetic and/or epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells, which together endow incipient metastatic cells with traits needed to generate macroscopic metastases. Recent advances provide provocative insights into these cell-biological and molecular changes, which have implications regarding the steps of the invasion-metastasis cascade that appear amenable to therapeutic targeting. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Morphologic and biochemical hallmarks of apoptosis.

            Apoptosis is characterised by a series of typical morphological features, such as shrinkage of the cell, fragmentation into membrane-bound apoptotic bodies and rapid phagocytosis by neighbouring cells. This paper reviews the current knowledge on the molecular mechanisms of apoptosis as they relate to the morphologic hallmarks and their implications for the detection of apoptosis in cardiac tissue. Activation of cysteine proteases called caspases plays a major role in the execution of apoptosis. These proteases selectively cleave vital cellular substrates, which results in apoptotic morphology and internucleosomal fragmentation of DNA by selectively activated DNases. In response to several pro-apoptotic signals, mitochondria release caspase activating factors, that initiate an escalating caspase cascade and commit the cell to die. Members of the Bcl-2 oncoprotein family control mitochondrial events and are able to prevent, or induce, both apoptotic and non-apoptotic types of cell death. This suggests that different types of cell death share common mechanisms in the early phases, whereas activation of caspases determines the phenotype of cell death. Detection of apoptotic cells in tissue samples currently relies on the TUNEL assay. TUNEL-positive cardiomyocytes show morphological features of apoptosis and the typical ladder pattern in DNA electrophoresis. Thus, provided that the staining protocol is carefully standardised, this quantitative methodology provides reproducible results of the occurrence of cardiomyocyte apoptosis in cardiac samples. Recently, potentially more specific assays based on analysis of DNA fragmentation or demonstration of caspase activation have been developed. Applicability of these assays to demonstrate cardiomyocyte apoptosis should be tested.
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              Transforming growth factor-beta in cancer and metastasis.

              Transforming growth factor-beta (TGF-beta) is a multifunctional regulatory polypeptide that is the prototypical member of a large family of cytokines that controls many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival. The actions of TGF-beta are dependent on several factors including cell type, growth conditions, and the presence of other polypeptide growth factors. One of the biological effects of TGF-beta is the inhibition of proliferation of most normal epithelial cells using an autocrine mechanism of action, and this suggests a tumor suppressor role for TGF-beta. Loss of autocrine TGF-beta activity and/or responsiveness to exogenous TGF-beta appears to provide some epithelial cells with a growth advantage leading to malignant progression. This suggests a pro-oncogenic role for TGF-beta in addition to its tumor suppressor role. During the early phase of epithelial tumorigenesis, TGF-beta inhibits primary tumor development and growth by inducing cell cycle arrest and apoptosis. In late stages of tumor progression when tumor cells become resistant to growth inhibition by TGF-beta due to inactivation of the TGF-beta signaling pathway or aberrant regulation of the cell cycle, the role of TGF-beta becomes one of tumor promotion. Resistance to TGF-beta-mediated inhibition of proliferation is frequently observed in multiple human cancers, as are various alterations in the complex TGF-beta signaling and cell cycle pathways. TGF-beta can exert effects on tumor and stromal cells as well as alter the responsiveness of tumor cells to TGF-beta to stimulate invasion, angiogenesis, and metastasis, and to inhibit immune surveillance. Because of the dual role of TGF-beta as a tumor suppressor and pro-oncogenic factor, members of the TGF-beta signaling pathway are being considered as predictive biomarkers for progressive tumorigenesis, as well as molecular targets for prevention and treatment of cancer and metastasis.
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                Author and article information

                Contributors
                huangrenbin518@163.com
                ying.gao@mtsu.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                27 July 2017
                27 July 2017
                2017
                : 7
                : 6704
                Affiliations
                [1 ]ISNI 0000 0004 1798 2653, GRID grid.256607.0, Department of Pharmacology, , Guangxi Medical University, ; Nanning, Guangxi 530021 China
                [2 ]ISNI 0000 0001 2111 6385, GRID grid.260001.5, Department of Biology and Tennessee Center for Botanical Medicine Research, , Middle Tennessee State University, ; Murfreesboro, TN 37132 USA
                Article
                7162
                10.1038/s41598-017-07162-3
                5532290
                28751740
                424725dd-b5cf-4140-a7b9-b0abba8df113
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 January 2017
                : 26 June 2017
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