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Nature. 2019 Mar;567(7748):341-346. doi: 10.1038/s41586-019-0993-x. Epub 2019 Mar 6.

Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma.

Shi Y1,2, Lim SK3,4,5, Liang Q3, Iyer SV1,2, Wang HY3, Wang Z1,2, Xie X1,2, Sun D1,2, Chen YJ1,2,6, Tabar V1,7, Gutin P1,7, Williams N3, De Brabander JK3, Parada LF8,9,10,11.

Author information

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.

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.

Comment in

PMID:
30842654
DOI:
10.1038/s41586-019-0993-x

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