2. Academic Validation
  3. Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma

Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma

  • Nature. 2019 Mar;567(7748):341-346. doi: 10.1038/s41586-019-0993-x.
Yufeng Shi 1 2,  S Kyun Lim 3 4 5,  Qiren Liang 3,  Swathi V Iyer 1 2,  Hua-Yu Wang 3,  Zilai Wang 1 2,  Xuanhua Xie 1 2,  Daochun Sun 1 2,  Yu-Jung Chen 1 2 6,  Viviane Tabar 1 7,  Philip Gutin 1 7,  Noelle Williams 3,  Jef K De Brabander 3,  Luis F Parada 8 9 10 11
Affiliations

Affiliations

  • 1 Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA.
  • 4 Department of Developmental Biology, UT Southwestern Medical Center, Dallas, TX, USA.
  • 5 Vivid Biosciences, Boston, MA, USA.
  • 6 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7 Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Brain Tumor Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA. paradal@mskcc.org.
  • 9 Cancer Biology & Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. paradal@mskcc.org.
  • 10 Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. paradal@mskcc.org.
  • 11 Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. paradal@mskcc.org.
PMID: 30842654 DOI: 10.1038/s41586-019-0993-x
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 F0F1 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.

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