Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma

Yufeng Shi, S. Kyun Lim, Qiren Liang, Swathi V. Iyer, Hua-Yu Wang, Zilai Wang, Xuanhua Xie, Daochun Sun, Yu-Jung Chen, Viviane Tabar, Philip Gutin, Noelle Williams, Jef K. Brabander and Luis F. Parada ()
Additional contact information
Yufeng Shi: Memorial Sloan Kettering Cancer Center
S. Kyun Lim: UT Southwestern Medical Center
Qiren Liang: UT Southwestern Medical Center
Swathi V. Iyer: Memorial Sloan Kettering Cancer Center
Hua-Yu Wang: UT Southwestern Medical Center
Zilai Wang: Memorial Sloan Kettering Cancer Center
Xuanhua Xie: Memorial Sloan Kettering Cancer Center
Daochun Sun: Memorial Sloan Kettering Cancer Center
Yu-Jung Chen: Memorial Sloan Kettering Cancer Center
Viviane Tabar: Memorial Sloan Kettering Cancer Center
Philip Gutin: Memorial Sloan Kettering Cancer Center
Noelle Williams: UT Southwestern Medical Center
Jef K. Brabander: UT Southwestern Medical Center
Luis F. Parada: Memorial Sloan Kettering Cancer Center

Nature, 2019, vol. 567, issue 7748, 341-346

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-0993-x

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