Reversing the Warburg effect as a treatment for glioblastoma

Ethan Poteet, Gourav Roy Choudhury, Ali Winters, Wenjun Li, Myoung Gwi Ryou, Ran Liu, Lin Tang, Anuja Ghorpade, Yi Wen, Fang Yuan, Stephen T. Keir, Hai Yan, Darell D. Bigner, James W. Simpkins, Shao Hua Yang

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Glioblastoma multiforme (GBM), like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect. Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in GBM cell lines. MB decreases GBM cell proliferation and halts the cell cycle in S phase. Through activation of AMP-activated protein kinase, MB inactivates downstream acetyl-CoA carboxylase and decreases cyclin expression. Structure-activity relationship analysis demonstrated that toluidine blue O, an MB derivative with similar bioenergetic actions, exerts similar action in GBM cell proliferation. In contrast, two other MB derivatives, 2-chlorophenothiazine and promethazine, exert no effect on cellular bioenergetics and do not inhibitGBMcell proliferation. MB inhibits cell proliferation in both temozolomidesensitive and -insensitive GBM cell lines. In a human GBM xenograft model, a single daily dosage of MB does not activate AMP-activated protein kinase signaling, and no tumor regression was observed. In summary, the current study provides the first in vitro proof of concept that reversal of Warburg effect might be a novel therapy for GBM.

Original languageEnglish
Pages (from-to)9153-9164
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number13
DOIs
StatePublished - 29 Mar 2013

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