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      Is Open Access

      Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth

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          Abstract

          Purpose

          The Epstein–Barr virus (EBV)-associated cancer nasopharyngeal carcinoma (NPC) is rare in Europe and North America but is a real public health problem in some regions of the world, such as southern Asia, North Africa, and for Inuit populations. Due to the anatomy and location of the nasopharynx, surgery is rarely used to treat primary NPC cancers. Treatment by radiotherapy, combined or not with chemotherapy, are efficient for primary tumors but often do not protect against fatal relapses or metastases.

          Methods

          Search for new therapeutic molecules through high content screening lead to the identification of Ivermectin (IVM) as a promising drug. IVM is a US Food and Drug Administration-approved macrocyclic lactone widely used as anthelmintic and insecticidal agent that has also shown protective effects against cancers.

          Results

          We show here that IVM has cytotoxic activity in vitro against NPC cells, in which it reduces MAPKs pathway activation through the inhibition PAK-1 activity. Moreover, all macrocyclic lactones tested and a PAK1 inhibitor are cytotoxic in vitro for EBV-positive and EBV-negative NPC tumor cells. We have also shown that IVM intraperitoneal repeated injections, at US Food and Drug Administration-approved doses, have no significant toxicity and decrease NPC subcutaneous tumors development in nude mice.

          Conclusion

          Macrocyclic lactones appear as promising molecules against NPC targeting PAK-1 with no detectable adverse effect.

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          Most cited references 22

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          A good practice guide to the administration of substances and removal of blood, including routes and volumes.

          This article is the result of an initiative between the European Federation of Pharmaceutical Industries Associations (EFPIA) and the European Centre for the Validation of Alternative Methods (ECVAM). Its objectives are to provide the researcher in the safety evaluation laboratory with an up-to-date, easy-to-use set of data sheets to aid in the study design process whilst at the same time affording maximum welfare considerations to the experimental animals. Although this article is targeted at researchers in the European Pharmaceutical Industry, it is considered that the principles underpinning the data sets and refinement proposals are equally applicable to all those who use these techniques on animals in their research, whether in research institutes, universities or other sectors of industry. The implications of this article may lead to discussion with regulators, such as those responsible for pharmacopoeial testing. There are numerous publications dealing with the administration of test substances and the removal of blood samples, and many laboratories also have their own "in-house" guidelines that have been developed by custom and practice over many years. Within European Union Directive 86/609EEC1 we have an obligation to refine experiments to cause the minimum amount of stress. We hope that this article will provide background data useful to those responsible for protocol design and review. This guide is based on peer-reviewed publications whenever possible, but where this is not possible we have used "in-house" data and the experience of those on the working party (as well as helpful comments submitted by the industry) for a final opinion. The guide also addresses the continuing need to refine the techniques associated with the administration of substances and the withdrawal of blood, and suggests ways of doing so. Data-sharing between laboratories should be encouraged to avoid duplication of animal work, as well as sharing practical skills concerning animal welfare and scientific problems caused by "overdosing" in some way or another. The recommendations in this guide refer to the "normal" animal, and special consideration is needed, for instance, during pregnancy and lactation. Interpretation of studies may be confounded when large volumes are administered or excessive sampling employed, particularly if anaesthetics are used. Copyright 2001 John Wiley & Sons, Ltd.
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            Nasopharyngeal carcinoma--review of the molecular mechanisms of tumorigenesis.

            Nasopharyngeal carcinoma (NPC) is a head and neck cancer rare throughout most of the world but common in certain geographic areas, such as southern Asia. While environmental factors and genetic susceptibility play important roles in NPC pathogenesis, the Epstein-Barr virus in particular has been implicated in the molecular abnormalities leading to NPC. There is upregulation of cellular proliferation pathways such as the Akt pathway, mitogen-activated protein kinases, and the Wnt pathway. Cell adhesion is compromised due to abnormal E-cadherin and beta-catenin function. Aberrations in cell cycle are due to dysregulation of factors such as p16, cyclin D1, and cyclin E. Anti-apoptotic mechanisms are also upregulated. There are multiple abnormalities unique to NPC that are potential targets for novel treatments.
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              Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells.

              p21-activated kinases (PAKs) are serine/threonine protein kinases that serve as important mediators of Rac and Cdc42 GTPase function as well as pathways required for Ras-driven tumorigenesis. PAK1 has been implicated in signaling by growth factor receptors and morphogenetic processes that control cell polarity, invasion, and actin cytoskeleton organization. To better understand the role of PAK1 in tumorigenesis, PAK1 genomic copy number and expression were determined for a large panel of breast, lung, and head and neck tumors. PAK1 genomic amplification at 11q13 was prevalent in luminal breast cancer, and PAK1 protein expression was associated with lymph node metastasis. Breast cancer cells with PAK1 genomic amplification rapidly underwent apoptosis after inhibition of this kinase. Strong nuclear and cytoplasmic PAK1 expression was also prevalent in squamous nonsmall cell lung carcinomas (NSCLCs), and selective PAK1 inhibition was associated with delayed cell-cycle progression in vitro and in vivo. NSCLC cells were profiled using a library of pathway-targeted small-molecule inhibitors, and several synergistic combination therapies, including combination with antagonists of inhibitor of apoptosis proteins, were revealed for PAK1. Dual inhibition of PAK1 and X chromosome-linked inhibitor of apoptosis efficiently increased effector caspase activation and apoptosis of NSCLC cells. Together, our results provide evidence for dysregulation of PAK1 in breast and squamous NSCLCs and a role for PAK1 in cellular survival and proliferation in these indications.
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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
                07 September 2018
                : 12
                : 2805-2814
                Affiliations
                [1 ]NeoVirTech, SAS, Institut for Advanced Technology in Life Science (ITAV), Toulouse, France, fgallardo@ 123456neovirtech.com
                [2 ]ITAV USR3505 CNRS/LBME, UMR 5099 CNRS, Toulouse, France
                [3 ]INSERM UMR 1037, CRCT, University of Toulouse, Toulouse, France
                [4 ]INSERM 1220, IRSD, University of Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France, anne-francoise.tilkin@ 123456inserm.fr
                Author notes
                Correspondence: Franck Gallardo, NeoVirTech, Institut des Technologies Avancées en sciences du Vivant, 1 Place Pierre Potier, Oncopôle, 31106 Toulouse, France, Tel +33 5 82 99 10 12, Email fgallardo@ 123456neovirtech.com
                Anne-Francoise Tilkin-Mariamé, Institut de recherche en santé digestive (IRSD), CHU Purpan BP3028, INSERM U1220, Bat 1B, 31024 Toulouse, France, Tel +33 5 62 74 61 42, Fax +33 5 62 74 45 74, Email anne-francoise.tilkin@ 123456inserm.fr
                Article
                dddt-12-2805
                10.2147/DDDT.S172538
                6135081
                © 2018 Gallardo 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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                Original Research

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