Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma Journal Article


Authors: Shi, Y.; Lim, S. K.; Liang, Q.; Iyer, S. V.; Wang, H. Y.; Wang, Z.; Xie, X.; Sun, D.; Chen, Y. J.; Tabar, V.; Gutin, P.; Williams, N.; De Brabander, J. K.; Parada, L. F.
Article Title: Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma
Abstract: Cancer-specific inhibitors that reflect the unique metabolic needs of cancer cells are rare. Here we describe Gboxin, a small molecule that specifically inhibits the growth of primary mouse and human glioblastoma cells but not that of mouse embryonic fibroblasts or neonatal astrocytes. Gboxin rapidly and irreversibly compromises oxygen consumption in glioblastoma cells. Gboxin relies on its positive charge to associate with mitochondrial oxidative phosphorylation complexes in a manner that is dependent on the proton gradient of the inner mitochondrial membrane, and it inhibits the activity of F 0 F 1 ATP synthase. Gboxin-resistant cells require a functional mitochondrial permeability transition pore that regulates pH and thus impedes the accumulation of Gboxin in the mitochondrial matrix. Administration of a metabolically stable Gboxin analogue inhibits glioblastoma allografts and patient-derived xenografts. Gboxin toxicity extends to established human cancer cell lines of diverse organ origin, and shows that the increased proton gradient and pH in cancer cell mitochondria is a mode of action that can be targeted in the development of antitumour reagents. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Journal Title: Nature
Volume: 567
Issue: 7748
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2019-03-21
Start Page: 341
End Page: 346
Language: English
DOI: 10.1038/s41586-019-0993-x
PUBMED: 30842654
PROVIDER: scopus
PMCID: PMC6655586
DOI/URL:
Notes: Source: Scopus
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MSK Authors
  1. Viviane S Tabar
    140 Tabar
  2. Philip H Gutin
    161 Gutin
  3. Luis F Parada
    14 Parada
  4. Yufeng Shi
    3 Shi
  5. Zilai Wang
    4 Wang
  6. Daochun Sun
    7 Sun
  7. Xuanhua Xie
    5 Xie
  8. Swathi Venkartraman Iyer
    1 Iyer
  9. Yu-Jung Chen
    1 Chen