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      In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems

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          Abstract

          Thalidomide, a drug known for its teratogenic side-effects, is used successfully to treat a variety of clinical conditions including leprosy and multiple myeloma. Intense efforts are underway to synthesize and identify safer, clinically relevant analogs. Here, we conduct a preliminary in vivo screen of a library of new thalidomide analogs to determine which agents demonstrate activity, and describe a cohort of compounds with anti-angiogenic properties, anti-inflammatory properties and some compounds which exhibited both. The combination of the in vivo zebrafish and chicken embryo model systems allows for the accelerated discovery of new, potential therapies for cancerous and inflammatory conditions.

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          A series of normal stages in the development of the chick embryo. 1951.

          Viktor Hamburger, Howard L. Hamilton (1992)
          Article 0 comments Cited 372 times – based on 0 reviews     Review now
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            Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide.

            A Lopez-Girona, D Mendy, T. Ito … (2012)
            Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.
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              Thalidomide‐induced teratogenesis: History and mechanisms

              Neil Vargesson (2015)
              Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man‐made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. Birth Defects Research (Part C) 105:140–156, 2015. © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 31 May 2016
                Publication date (Electronic): 22 April 2016
                Volume: 7
                Issue: 22
                Pages: 33237-33245
                Affiliations
                1 School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
                2 Molecular Pharmacology Section, Genitourinary Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
                3 Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA
                4 Current address: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Manchester, UK
                Author notes
                Article
                Publisher ID: 8909
                DOI: 10.18632/oncotarget.8909
                PMC ID: 5078090
                PubMed ID: 27120781
                SO-VID: cc55a633-a387-4d44-9197-438b5f282cad
                Copyright © Copyright: © 2016 Beedie et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 21 September 2015
                Date accepted : 31 March 2016
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: angiogenesis,inflammation,thalidomide,cancer,teratogenesis
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: angiogenesis, inflammation, thalidomide, cancer, teratogenesis

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