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      5-( Bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid (BHIMHA): showing a strategy of designing drug to block lung metastasis of tumors

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          Abstract

          Early metastasis is still the most recalcitrant factor in the treatment of lung cancer patients. By analyzing the structures and comparing the docking scores of the known pharmacophores, the authors of this paper designed 5-( bis(3-(2-hydroxyethyl)-1H-indol-2-yl)methyl)-2-hydroxybenzoic acid (BHIMHA) as a promising lead compound to develop metastasis inhibitors. In vitro 5, 10, and 20 µM of BHIMHA concentration dependently inhibited the migration and invasion of A549 cells. In vivo 0.4, 2.0, and 8.9 µmol/kg of BHIMHA dose dependently inhibited the metastasis of LLC (Lewis Lung Carcinoma) toward lung. In vivo, 2 µmol/kg of BHIMHA showed additional actions of slowing the growth of the primary tumor of C57BL/6 mice and S180 mice as well as inhibiting xylene-induced ear edema of the mice. Therefore, BHIMHA simultaneously blocked tumor metastasis toward lung, slowed the primary tumor growth, and limited the inflammation. These pharmacological actions were correlated with the inhibition of PKCα and NF-κB expression.

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          Most cited references 21

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          PKC and the control of localized signal dynamics.

          Networks of signal transducers determine the conversion of environmental cues into cellular actions. Among the main players in these networks are protein kinases, which can acutely and reversibly modify protein functions to influence cellular events. One group of kinases, the protein kinase C (PKC) family, have been increasingly implicated in the organization of signal propagation, particularly in the spatial distribution of signals. Examples of where and how various PKC isoforms direct this tier of signal organization are becoming more evident.
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            Protein kinase C and cancer: what we know and what we do not.

             R Garg,  L Benedetti,  M Abera (2014)
            Since their discovery in the late 1970s, protein kinase C (PKC) isozymes represent one of the most extensively studied signaling kinases. PKCs signal through multiple pathways and control the expression of genes relevant for cell cycle progression, tumorigenesis and metastatic dissemination. Despite the vast amount of information concerning the mechanisms that control PKC activation and function in cellular models, the relevance of individual PKC isozymes in the progression of human cancer is still a matter of controversy. Although the expression of PKC isozymes is altered in multiple cancer types, the causal relationship between such changes and the initiation and progression of the disease remains poorly defined. Animal models developed in the last years helped to better understand the involvement of individual PKCs in various cancer types and in the context of specific oncogenic alterations. Unraveling the enormous complexity in the mechanisms by which PKC isozymes have an impact on tumorigenesis and metastasis is key for reassessing their potential as pharmacological targets for cancer treatment.
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              Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice.

              Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                16 February 2016
                : 10
                : 711-721
                Affiliations
                [1 ]Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China
                [2 ]Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing, People’s Republic of China
                [3 ]Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
                [4 ]Ludwig Center for Cancer Genetics and Therapeutics Kimmel Cancer Center, Johns Hopkins University School of Medicine, USA
                Author notes
                Correspondence: Shiqi Peng; Ming Zhao, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, No 10 Xitoutiao, You An Men, Beijing 100069, People’s Republic of China, Tel +86 10 8391 1528, Fax +86 10 8391 1535, Email sqpeng@ 123456bjmu.edu.cn ; mingzhao@ 123456bjmu.edu.cn
                Article
                dddt-10-711
                10.2147/DDDT.S93570
                4762582
                26937173
                © 2016 Gan et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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