Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma

Yufeng Shi, Sang kyun Lim, Qiren Liang, Swathi V. Iyer, Hua Yu Wang, Zilai Wang, Xuanhua Xie, Daochun Sun, Yu Jung Chen, Viviane Tabar, Philip Gutin, Noelle S Williams, Jef K De Brabander, Luis F. Parada

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)341-346
Number of pages6
JournalNature
Volume567
Issue number7748
DOIs
StatePublished - Mar 21 2019

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Oxidative Phosphorylation
Glioblastoma
Neoplasms
Proton-Translocating ATPases
Mitochondrial Membranes
Heterografts
Astrocytes
Allografts
Protons
Mitochondria
Fibroblasts
Oxygen
Cell Line
Growth

ASJC Scopus subject areas

  • General

Cite this

Shi, Y., Lim, S. K., Liang, Q., Iyer, S. V., Wang, H. Y., Wang, Z., ... Parada, L. F. (2019). Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. Nature, 567(7748), 341-346. https://doi.org/10.1038/s41586-019-0993-x

Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. / Shi, Yufeng; Lim, Sang kyun; Liang, Qiren; Iyer, Swathi V.; Wang, Hua Yu; Wang, Zilai; Xie, Xuanhua; Sun, Daochun; Chen, Yu Jung; Tabar, Viviane; Gutin, Philip; Williams, Noelle S; De Brabander, Jef K; Parada, Luis F.

In: Nature, Vol. 567, No. 7748, 21.03.2019, p. 341-346.

Research output: Contribution to journalArticle

Shi, Y, Lim, SK, Liang, Q, Iyer, SV, Wang, HY, Wang, Z, Xie, X, Sun, D, Chen, YJ, Tabar, V, Gutin, P, Williams, NS, De Brabander, JK & Parada, LF 2019, 'Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma', Nature, vol. 567, no. 7748, pp. 341-346. https://doi.org/10.1038/s41586-019-0993-x
Shi, Yufeng ; Lim, Sang kyun ; Liang, Qiren ; Iyer, Swathi V. ; Wang, Hua Yu ; Wang, Zilai ; Xie, Xuanhua ; Sun, Daochun ; Chen, Yu Jung ; Tabar, Viviane ; Gutin, Philip ; Williams, Noelle S ; De Brabander, Jef K ; Parada, Luis F. / Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma. In: Nature. 2019 ; Vol. 567, No. 7748. pp. 341-346.
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