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      Gallium Maltolate Disrupts Tumor Iron Metabolism and Retards the Growth of Glioblastoma by Inhibiting Mitochondrial Function and Ribonucleotide Reductase

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          Abstract

          Gallium, a metal with antineoplastic activity, binds transferrin (Tf) and enters tumor cells via Tf receptor1 (TfR1); it disrupts iron homeostasis leading to cell death. We hypothesized that TfR1 on brain microvascular endothelial cells (BMECs) would facilitate Tf-Ga transport into the brain enabling it to target TfR-bearing glioblastoma. We show that U-87 MG and D54 glioblastoma cell lines and multiple glioblastoma stem cell (GSCs) lines express TfRs and that their growth is inhibited by gallium maltolate (GaM) in vitro. After 24-h of incubation with GaM, cells displayed a loss of mitochondrial reserve capacity followed by a dose-dependent decrease in oxygen consumption and a decrease in the activity of the iron-dependent M2 subunit of ribonucleotide reductase (RRM2). Immunohistochemical staining of rat and human tumor-bearing brains showed that glioblastoma, but not normal glial cells, expressed TfR1 and RRM2 and that glioblastoma expressed greater levels of H- and L-ferritin than normal brain. In an orthotopic U-87 MG glioblastoma xenograft rat model, GaM retarded the growth of brain tumors relative to untreated control (p=0.0159) and reduced tumor mitotic figures (p=0.045). Tumors in GaM-treated animals displayed an upregulation of TfR1 expression relative to control animals thus indicating that gallium produced tumor iron deprivation. GaM also inhibited iron uptake and upregulated TfR1 expression in U-87 MG and D54 cells in vitro. We conclude that GaM enters the brain via TfR1 on BMECs and targets iron metabolism in glioblastoma in vivo, thus inhibiting tumor growth. Further development of novel gallium compounds for brain tumor treatment is warranted.

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          Author and article information

          Journal
          101132535
          30097
          Mol Cancer Ther
          Mol. Cancer Ther.
          Molecular cancer therapeutics
          1535-7163
          1538-8514
          3 April 2018
          28 March 2018
          June 2018
          01 June 2019
          : 17
          : 6
          : 1240-1250
          Affiliations
          [1 ]Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin
          [2 ]Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin
          [3 ]Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin
          [4 ]Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
          [5 ]Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin
          Author notes
          Corresponding author: Christopher R. Chitambar, MD, Division of Hematology and Oncology, Medical College of Wisconsin, 9200 W. Wisconsin Ave, Milwaukee, WI 53226, Phone: 414-805-4600, FAX: 414-805-4606, chitambr@ 123456mcw.edu
          Article
          PMC5984712 PMC5984712 5984712 nihpa956253
          10.1158/1535-7163.MCT-17-1009
          5984712
          29592883
          8f69ed60-759c-4408-b50f-bbff8439bf4d
          History
          Categories
          Article

          gallium maltolate,iron metabolism,glioblastoma
          gallium maltolate, iron metabolism, glioblastoma

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