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, Shao Hua
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
C2 - 23408428
AN - SCOPUS:84876004187
SN - 0021-9258
VL - 288
SP - 9153
EP - 9164
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 13
ER -