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      Anticancer effects of a non-narcotic opium alkaloid medicine, papaverine, in human glioblastoma cells

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          Abstract

          The interaction between high-mobility group box 1 protein (HMGB1) and receptor for advanced glycation end products (RAGE) is important for tumor cell growth. We investigated the tumor biological effects of HMGB1 and RAGE interaction. Previously, we identified an inhibitor of HMGB1/RAGE interaction, papaverine (a non-narcotic opium alkaloid), using a unique drug design system and drug repositioning approach. In the present study, we examined the anticancer effects of papaverine in human glioblastoma (GBM) temozolomide (TMZ; as a first-line anticancer medicine)-sensitive U87MG and TMZ-resistant T98G cells. HMGB1 supplementation in the culture medium promoted tumor cell growth in T98G cells, and this effect was canceled by papaverine. In addition, papaverine in T98G cells suppressed cancer cell migration. As an HMGB1/RAGE inhibitor, papaverine also significantly inhibited cell proliferation in U87MG and T98G cells. The effects of papaverine were evaluated in vivo in a U87MG xenograft mouse model by determining tumor growth delay. The results indicate that papaverine, a smooth muscle relaxant, is a potential anticancer drug that may be useful in GBM chemotherapy.

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          Temozolomide: mechanisms of action, repair and resistance.

          Glioblastoma multiforme is the most common aggressive adult primary tumour of the central nervous system. Treatment includes surgery, radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. TMZ is an alkylating agent prodrug, delivering a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine (O6-MeG) can be removed by methylguanine methyltransferase (MGMT; direct repair) in tumours expressing this protein, or tolerated in mismatch repair-deficient (MMR-) tumours. Thus MGMT or MMR deficiency confers resistance to TMZ. Inherent- and acquired resistance to TMZ present major obstacles to successful treatment. Strategies devised to thwart resistance and enhance response to TMZ, including inhibition of DNA repair mechanisms which contribute to TMZ resistance, are under clinical evaluation. Depletion of MGMT prior to alkylating agent chemotherapy prevents O6-MeG repair; thus, MGMT pseudosubstrates O6-benzylguanine and lomeguatrib are able to sensitise tumours to TMZ. Disruption of base excision repair (BER) results in persistence of potentially lethal N7- and N3- purine lesions contributing significantly to TMZ cytoxicity particularly when O6-MeG adducts are repaired or tolerated. Several small molecule inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1), a critical BER protein are yielding promising results clinically, both in combination with TMZ and as single agent chemotherapy in patients whose tumours possess homologous recombination DNA repair defects. Another validated, but as yet preclinical protein target, mandatory to BER is abasic (AP) endonuclease-1 (APE-1); in preclinical tests, APE-1 inhibition potentiates TMZ activity. An alternative strategy is synthesis of a molecule, evoking an irrepairable cytotoxic O6-G lesion. Preliminary efforts to achieve this goal are described.
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            High-mobility group box 1 and cancer.

            High-mobility group box 1 protein (HMGB1), a chromatin associated nuclear protein and extracellular damage associated molecular pattern molecule (DAMP), is an evolutionarily ancient and critical regulator of cell death and survival. Overexpression of HMGB1 is associated with each of the hallmarks of cancer including unlimited replicative potential, ability to develop blood vessels (angiogenesis), evasion of programmed cell death (apoptosis), self-sufficiency in growth signals, insensitivity to inhibitors of growth, inflammation, tissue invasion and metastasis. Our studies and those of our colleagues suggest that HMGB1 is central to cancer (abnormal wound healing) and many of the findings in normal wound healing as well. Here, we focus on the role of HMGB1 in cancer, the mechanisms by which it contributes to carcinogenesis, and therapeutic strategies based on targeting HMGB1. Copyright 2009 Elsevier B.V. All rights reserved.
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              Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism

              Oxygen tension plays a critical role in the response to radiation therapy (RT). Here we show that hypoxic tumors can be sensitized to RT by targeting mitochondrial respiration. We identified the 150-year-old FDA-approved drug papaverine as a mitochondrial complex I inhibitor. A single dose of the drug prior to RT alleviates hypoxia in model tumors and strikingly enhances the response to RT. Well-oxygenated normal tissues are not radiosensitized. Removal of papaverine’s phosphodiesterase 10A inhibitory activity by structural modification has identified potentially safer generation of complex I-inhibiting radiosensitizers. Tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. An acute increase in tumor oxygenation before radiation treatment should therefore significantly improve the tumor cell kill after radiation. Efforts to increase oxygen delivery to the tumor have not shown positive clinical results. Here we show that targeting mitochondrial respiration results in a significant reduction of the tumor cells’ demand for oxygen, leading to increased tumor oxygenation and radiation response. We identified an activity of the FDA-approved drug papaverine as an inhibitor of mitochondrial complex I. We also provide genetic evidence that papaverine’s complex I inhibition is directly responsible for increased oxygenation and enhanced radiation response. Furthermore, we describe derivatives of papaverine that have the potential to become clinical radiosensitizers with potentially fewer side effects. Importantly, this radiosensitizing strategy will not sensitize well-oxygenated normal tissue, thereby increasing the therapeutic index of radiotherapy.
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                Author and article information

                Contributors
                Role: InvestigationRole: Validation
                Role: Investigation
                Role: Validation
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – original draft
                Role: ConceptualizationRole: Formal analysisRole: Validation
                Role: ConceptualizationRole: Formal analysisRole: Validation
                Role: ConceptualizationRole: Formal analysisRole: Validation
                Role: ConceptualizationRole: Funding acquisitionRole: Supervision
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                17 May 2019
                2019
                : 14
                : 5
                : e0216358
                Affiliations
                [1 ] Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
                [2 ] National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
                [3 ] Department of Neurosurgery, Jikei University School of Medicine, Minato-ku, Tokyo, Japan
                [4 ] Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
                [5 ] Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, Japan
                Sechenov First Medical University, RUSSIAN FEDERATION
                Author notes

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

                Author information
                http://orcid.org/0000-0002-2239-6208
                Article
                PONE-D-18-35172
                10.1371/journal.pone.0216358
                6524804
                31100066
                61c49089-08df-4fc1-8458-2e55299f428e
                © 2019 Inada 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
                : 9 December 2018
                : 18 April 2019
                Page count
                Figures: 2, Tables: 2, Pages: 9
                Funding
                This work was supported by a JSPS KAKENHI grant number 26670648 (T.A.) and an Education Research Fund for Tokyo University of Science (A.S. and S.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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