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      Design and development of ICCA as a dual inhibitor of GPIIb/IIIa and P-selectin receptors

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          Abstract

          Background

          The impact of upregulation of platelet membrane glycoprotein (GP)IIb/IIIa and P-selectin on the onset of arterial thrombosis, venous thrombosis, and cancer encourages to hypothesize that dual inhibitor of GPIIb/IIIa and P-selectin receptors should simultaneously inhibit arterial thrombosis, block venous thrombosis, and slow tumor growth.

          Methods

          For this reason, the structural characteristics and the CDOCKER interaction energies of 12 carbolines were analyzed. This led to the design of 1-(4-isopropyl-phenyl)- β-carboline-3-carboxylic acid (ICCA) as a promising inhibitor of GPIIb/IIIa and P-selectin receptors.

          Results

          The synthetic route provided ICCA in 48% total yield and 99.6% high-performance liquid chromatography purity. In vivo 5 μmol/kg oral ICCA downregulated GPIIb/IIIa and P-selectin expression thereby inhibited arterial thrombosis, blocked venous thrombosis, and slowed down tumor growth, but did not damage the kidney and the liver.

          Conclusion

          Therefore, ICCA could be a promising candidate capable of downregulating GPIIb/IIIa and P-selectin receptors, inhibiting arterial thrombosis, blocking venous thrombosis, and slowing down tumor growth.

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          Most cited references 30

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          The platelet-cancer loop.

          The relationship between cancer and thrombosis has been established since 1865 when Armand Trousseau described superficial thrombophlebitis as forewarning sign of occult visceral malignancy. Platelets are the primary hemostatic tool and play a primordial role in cancer-induced thrombosis. Tumor-induced numerical and functional platelet abnormalities have been described in conjunction to changes in coagulation. Such changes are reported even in the absence of clinically detectable thrombosis and correlate with tumor progression and metastasis. Reciprocally, platelets seem to interplay with the tumors and the immune system, both directly and indirectly favoring tumor progressions, tethering and distant spread. A number of growth factors supporting tumor growth, angiogenesis and metastasis are released from the platelets. A reciprocating loop of tumor-induced platelet activation/platelet-induced tumor growth and dissemination is initiated, acting as a thrombosis trigger/tumor amplifier. Recent studies have demonstrated that the use of anti-platelet agents can break this loop resulting in a reduction of short-term risk for incident cancer, cancer mortality and metastasis. The beneficial effect in reduction in cancer-induced thrombosis remains to be established. The current review aims at shedding the light on the intimate reciprocal cross-talk between platelets and cancer and on exploring the potential beneficial effect of anti-platelet agents in breaking the deadly loop of tumor amplification. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.
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            The role of platelets in the tumor microenvironment: From solid tumors to leukemia.

            Platelets are increasingly being recognized for promoting tumor growth and metastasis. Many cells derived from solid tumors have the ability to aggregate platelets, and this ability correlates with their metastatic potential. Over the past half century, our understanding of tumor cell-induced platelet aggregation (TCIPA) has grown beyond the simple concept that tumor cell-containing microthrombi mechanically embolize the microvasculature. Tumor cell-activated platelets secrete a multitude of factors that reciprocally act on tumor cells, as well as other cells within the tumor microenvironment; thus, affecting both parenychma and tumor-associated stroma. In this review, we summarize the current knowledge of tumor cell-platelet interactions and their influence on the tumor microenvironment, including how these interactions impact neoplastic epithelial cells, endothelial cells, pericytes, fibroblasts, immune cells, and early metastatic niches. In addition, we review the current knowledge of platelet-cancer cell interactions within hematological malignancies and speculate on how platelets may influence the leukemic microenvironment. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.
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              Novel anti-inflammatory therapies for the treatment of atherosclerosis.

              The underlying role of inflammation in atherosclerosis has been characterized. However, current treatment of coronary artery disease (CAD) predominantly consists of targeted reductions in serum lipoprotein levels rather than combating the deleterious effects of acute and chronic inflammation. Vascular inflammation acts by a number of different molecular and cellular pathways to contribute to atherogenesis. Over the last decades, both basic studies and clinical trials have provided evidence for the potential benefits of treatment of inflammation in CAD. During this period, development of pharmacotherapies directed towards inflammation in atherosclerosis has accelerated quickly. This review will highlight specific therapies targeting interleukin-1β (IL-1β), P-selectin and 5-lipoxygenase (5-LO). It will also aim to examine the anti-inflammatory effects of serpin administration, colchicine and intravenous HDL-directed treatment of CAD. We summarize the mechanistic rationale and evidence for these novel anti-inflammatory treatments at both the experimental and clinical levels.
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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
                2018
                09 July 2018
                : 12
                : 2097-2110
                Affiliations
                [1 ]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, Beijing, People’s Republic of China, sqpeng@ 123456bjmu.edu.cn ; mingzhao@ 123456bjmu.edu.cn
                [2 ]Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan, sqpeng@ 123456bjmu.edu.cn ; mingzhao@ 123456bjmu.edu.cn
                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; +86 10 8391 1535, Fax +86 10 8391 1533; +86 10 8391 1533, Email sqpeng@ 123456bjmu.edu.cn ; mingzhao@ 123456bjmu.edu.cn
                Article
                dddt-12-2097
                10.2147/DDDT.S169238
                6042529
                © 2018 Chen 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.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                thrombosis, cancer, gpiib/iiia, p-selectin

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