Gallium Maltolate Disrupts Tumor Iron Metabolism and Retards the Growth of Glioblastoma by Inhibiting Mitochondrial Function and Ribonucleotide Reductase. Mol Cancer Ther 2018 Jun;17(6):1240-1250
Date
03/30/2018Pubmed ID
29592883Pubmed Central ID
PMC5984712DOI
10.1158/1535-7163.MCT-17-1009Scopus ID
2-s2.0-85048073666 (requires institutional sign-in at Scopus site) 38 CitationsAbstract
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 (BMEC) 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 (GSC) lines express TfRs, and that their growth is inhibited by gallium maltolate (GaM) in vitro After 24 hours 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). IHC 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. Mol Cancer Ther; 17(6); 1240-50. ©2018 AACR.
Author List
Chitambar CR, Al-Gizawiy MM, Alhajala HS, Pechman KR, Wereley JP, Wujek R, Clark PA, Kuo JS, Antholine WE, Schmainda KMAuthors
Mona Al-Gizawiy PhD Assistant Professor in the Biophysics department at Medical College of WisconsinKathleen M. Schmainda PhD Professor in the Biophysics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntineoplastic Agents
Brain
Cell Line, Tumor
Disease Models, Animal
Glioblastoma
Heterografts
Humans
Immunohistochemistry
Iron
Male
Mitochondria
Organometallic Compounds
Pyrones
Rats
Receptors, Transferrin
Ribonucleoside Diphosphate Reductase
Ribonucleotide Reductases
