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      Comparative oncology approach to drug repurposing in osteosarcoma

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          Abstract

          Background

          Osteosarcoma is an orphan disease for which little improvement in survival has been made since the late 1980s. New drug discovery for orphan diseases is limited by the cost and time it takes to develop new drugs. Repurposing already approved FDA-drugs can help overcome this limitation. Another limitation of cancer drug discovery is the lack of preclinical models that accurately recapitulate what occurs in humans. For OS using dogs as a model can minimize this limitation as OS in canines develops spontaneously, is locally invasive and metastasizes to the lungs as it does in humans.

          Methods

          In our present work we used high-throughput screens to identify drugs from a library of 2,286 FDA-approved drugs that demonstrated selective growth inhibition against both human and canine OS cell lines. The identified lead compound was then tested for synergy with 7 other drugs that have demonstrated activity against OS. These results were confirmed with in vitro assays and an in vivo murine model of OS.

          Results

          We identified 13 drugs that demonstrated selective growth inhibition against both human and canine OS cell lines. Auranofin was selected for further in vitro combination drug screens. Auranofin showed synergistic effects with vorinostat and rapamycin on OS viability and apoptosis induction. Auranofin demonstrated single-agent growth inhibition in both human and canine OS xenografts, and cooperative growth inhibition was observed in combination with rapamycin or vorinostat. There was a significant decrease in Ki67-positive cells and an increase in cleaved caspase-3 levels in tumor tissues treated with a combination of auranofin and vorinostat or rapamycin.

          Conclusions

          Auranofin, alone or in combination with rapamycin or vorinostat, may be useful new treatment strategies for OS. Future studies may evaluate the efficacy of auranofin in dogs with OS as a prelude to human clinical evaluation.

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          Most cited references40

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          Histone Deacetylase Inhibitors in Clinical Studies as Templates for New Anticancer Agents

          Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing a wide variety of inhibitors. HDAC inhibitors interfere with HDAC activity and regulate biological events, such as cell cycle, differentiation and apoptosis in cancer cells. As a result, HDAC inhibitor-based therapies have gained much attention for cancer treatment. To date, the FDA has approved three HDAC inhibitors for cutaneous/peripheral T-cell lymphoma and many more HDAC inhibitors are in different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. In the intensifying efforts to discover new, hopefully more therapeutically efficacious HDAC inhibitors, molecular modeling-based rational drug design has played an important role in identifying potential inhibitors that vary in molecular structures and properties. In this review, we summarize four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.
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            Thioredoxin reductase.

            The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide-disulphide oxidoreductases with mechanistic and sequence identity, including a conserved -Cys-Val-Asn-Val-Gly-Cys- redox catalytic site, to glutathione reductases. TrxRs catalyse the NADPH-dependent reduction of the redox protein thioredoxin (Trx), as well as of other endogenous and exogenous compounds. The broad substrate specificity of mammalian TrxRs is due to a second redox-active site, a C-terminal -Cys-SeCys- (where SeCys is selenocysteine), that is not found in glutathione reductase or Escherichia coli TrxR. There are currently two confirmed forms of mammalian TrxRs, TrxR1 and TrxR2, and it is possible that other forms will be identified. The availability of Se is a key factor determining TrxR activity both in cell culture and in vivo, and the mechanism(s) for the incorporation of Se into TrxRs, as well as the regulation of TrxR activity, have only recently begun to be investigated. The importance of Trx to many aspects of cell function make it likely that TrxRs also play a role in protection against oxidant injury, cell growth and transformation, and the recycling of ascorbate from its oxidized form. Since TrxRs are able to reduce a number of substrates other than Trx, it is likely that additional biological effects will be discovered for TrxR. Furthermore, inhibiting TrxR with drugs may lead to new treatments for human diseases such as cancer, AIDS and autoimmune diseases.
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              Molecular aspects of cancer cell resistance to chemotherapy.

              Cancer cell resistance to chemotherapy is still a heavy burden that impairs treatment of cancer patients. Both intrinsic and acquired resistance results from the numerous genetic and epigenetic changes occurring in cancer cells. Most of the hallmarks of cancer cells provide general mechanisms to sustain stresses such as the ones induced by chemotherapeutic drugs. Moreover, specific changes in the target bring resistance to specific drugs like modification in nucleotide synthesis enzymes upon anti-metabolite exposure, in microtubule composition upon spindle poison treatment, in topoisomerase activity upon topoisomerase inhibitor incubation or in intracellular signaling pathways when targeting tyrosine kinase receptors. Finally, the stemness properties of a few cancer cells as well as components of the tumor stroma, like fibroblasts and tumor-associated macrophages but also hypoxia, also help tumor to resist to anticancer agents. These processes provide an additional level of complexity to the understanding of the tumor resistance phenomenon. This review aims to describe the different general mechanisms as well as some examples of specific on target modifications inducing cancer cell resistance to chemotherapy at the molecular level. Perspectives to develop more efficient treatment, using genomic signature or more specific biomarkers to characterize putative resistance mechanisms in patients before choosing the more appropriate treatment, will also be discussed. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: InvestigationRole: Writing – original draft
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: Data curationRole: Formal analysisRole: Methodology
                Role: Formal analysisRole: Writing – review & editing
                Role: Project administrationRole: Resources
                Role: Project administration
                Role: ConceptualizationRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisition
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: ResourcesRole: SupervisionRole: Writing – original draft
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 March 2018
                2018
                : 13
                : 3
                : e0194224
                Affiliations
                [1 ] Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America
                [2 ] High Throughput Screening Laboratory, University of Kansas Cancer Center, University of Kansas, Lawrence, Kansas, United States of America
                [3 ] University of Kansas Cancer Center, Kansas City, Kansas, United States of America
                [4 ] Biotechnology Innovation and Optimization Center, University of Kansas, Lawrence, Kansas, United States of America
                [5 ] Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, Kansas, United States of America
                [6 ] Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado, United States of America
                [7 ] University of Colorado Comprehensive Cancer Center, Aurora, Colorado, United States of America
                [8 ] Department of Pediatrics, University of Missouri Kansas City, Kansas City, Missouri, United States of America
                [9 ] Department of Pharmacology, Toxicology and Therapeutics, University of Kansas, Kansas City, Kansas, United States of America
                [10 ] Arkansas Children’s Hospital, Little Rock, Arkansas, United States of America
                [11 ] Division of Hematology and Oncology, Children’s Mercy Hospital and Clinics, Kansas City, Missouri, United States of America
                University of South Alabama Mitchell Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-9245-1359
                Article
                PONE-D-17-26263
                10.1371/journal.pone.0194224
                5868798
                29579058
                35d50a50-3dc9-4470-84fc-482a7dab69d1
                © 2018 Parrales et al

                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
                : 12 July 2017
                : 27 February 2018
                Page count
                Figures: 5, Tables: 1, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: NIH R01 CA176735
                Award Recipient :
                Funded by: Midwest Cancer Alliance
                Award Recipient :
                This work was supported by the National Institute of Health P30 CA168524 (Roy A Jenson- grant for the University of Kansas Cancer Center), https://www.nih.gov/; National Institute of Health CA174735 (TI), https://www.nih.gov/; Midwest Cancer Alliance (JF), http://www.midwestcanceralliance.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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