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      Comparative oncology approach to drug repurposing in osteosarcoma.

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          Abstract

          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.

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

          Madhusoodanan Mottamal, Shilong Zheng, Tien Huang … (2015)
          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.
          Article 0 comments Cited 198 times – based on 0 reviews     Review now
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            Thioredoxin reductase.

            D Mustacich, G Powis (2000)
            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.

              Magali Rebucci, Carine Michiels (2013)
              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

                Journal
                Journal ID (iso-abbrev): PLoS One
                Title: PloS one
                Publisher: Public Library of Science (PLoS)
                ISSN (Electronic): 1932-6203
                ISSN (Print): 1932-6203
                Publication date (Electronic): 2018
                Volume: 13
                Issue: 3
                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.
                Article
                Publisher Item ID: PONE-D-17-26263
                DOI: 10.1371/journal.pone.0194224
                PMC ID: 5868798
                PubMed ID: 29579058
                SO-VID: 35d50a50-3dc9-4470-84fc-482a7dab69d1
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