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, Shaohua Yang

Research output: Contribution to journalArticleResearchpeer-review

39 Citations (Scopus)

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

Fingerprint

Methylene Blue
Glioblastoma
Cell proliferation
Energy Metabolism
AMP-Activated Protein Kinases
Cells
Cell Proliferation
Promethazine
Derivatives
Acetyl-CoA Carboxylase
Cell Line
Tolonium Chloride
Cyclins
Glycolysis
Structure-Activity Relationship
S Phase
Heterografts
Oxygen Consumption
Tumors
Lactic Acid

Cite this

Poteet, Ethan ; Choudhury, Gourav Roy ; Winters, Ali ; Li, Wenjun ; Ryou, Myoung Gwi ; Liu, Ran ; Tang, Lin ; Ghorpade, Anuja ; Wen, Yi ; Yuan, Fang ; Keir, Stephen T. ; Yan, Hai ; Bigner, Darell D. ; Simpkins, James W. ; Yang, Shaohua. / Reversing the Warburg effect as a treatment for glioblastoma. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 13. pp. 9153-9164.
@article{f991c9bf0a294ae5b1c3cf6b1359bf6a,
title = "Reversing the Warburg effect as a treatment for glioblastoma",
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.",
author = "Ethan Poteet and Choudhury, {Gourav Roy} and Ali Winters and Wenjun Li and Ryou, {Myoung Gwi} and Ran Liu and Lin Tang and Anuja Ghorpade and Yi Wen and Fang Yuan and Keir, {Stephen T.} and Hai Yan and Bigner, {Darell D.} and Simpkins, {James W.} and Shaohua Yang",
year = "2013",
month = "3",
day = "29",
doi = "10.1074/jbc.M112.440354",
language = "English",
volume = "288",
pages = "9153--9164",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "13",

}

Poteet, E, Choudhury, GR, Winters, A, Li, W, Ryou, MG, Liu, R, Tang, L, Ghorpade, A, Wen, Y, Yuan, F, Keir, ST, Yan, H, Bigner, DD, Simpkins, JW & Yang, S 2013, 'Reversing the Warburg effect as a treatment for glioblastoma', Journal of Biological Chemistry, vol. 288, no. 13, pp. 9153-9164. https://doi.org/10.1074/jbc.M112.440354

Reversing the Warburg effect as a treatment for glioblastoma. / Poteet, Ethan; Choudhury, Gourav Roy; Winters, Ali; Li, Wenjun; Ryou, Myoung Gwi; Liu, Ran; Tang, Lin; Ghorpade, Anuja; Wen, Yi; Yuan, Fang; Keir, Stephen T.; Yan, Hai; Bigner, Darell D.; Simpkins, James W.; Yang, Shaohua.

In: Journal of Biological Chemistry, Vol. 288, No. 13, 29.03.2013, p. 9153-9164.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Reversing the Warburg effect as a treatment for glioblastoma

AU - Poteet, Ethan

AU - Choudhury, Gourav Roy

AU - Winters, Ali

AU - Li, Wenjun

AU - Ryou, Myoung Gwi

AU - Liu, Ran

AU - Tang, Lin

AU - Ghorpade, Anuja

AU - Wen, Yi

AU - Yuan, Fang

AU - Keir, Stephen T.

AU - Yan, Hai

AU - Bigner, Darell D.

AU - Simpkins, James W.

AU - Yang, Shaohua

PY - 2013/3/29

Y1 - 2013/3/29

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84876004187&partnerID=8YFLogxK

U2 - 10.1074/jbc.M112.440354

DO - 10.1074/jbc.M112.440354

M3 - Article

VL - 288

SP - 9153

EP - 9164

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 13

ER -