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 inhibit GBM cell proliferation. MB inhibits cell proliferation in both temozolomide-sensitive 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.
authors: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors: Ethan
authors: E
authors: Poteet
authors: Gourav Roy
authors: GR
authors: Choudhury
authors: Ali
authors: A
authors: Winters
authors: Wenjun
authors: W
authors: Li
authors: Myoung-Gwi
authors: MG
authors: Ryou
authors: Ran
authors: R
authors: Liu
authors: Lin
authors: L
authors: Tang
authors: Anuja
authors: A
authors: Ghorpade
authors: Yi
authors: Y
authors: Wen
authors: Fang
authors: F
authors: Yuan
authors: Stephen T
authors: ST
authors: Keir
authors: Hai
authors: H
authors: Yan
authors: Darell D
authors: DD
authors: Bigner
authors: James W
authors: JW
authors: Simpkins
authors: Shao-Hua
authors: SH
authors: Yang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001932:Brain Neoplasms / Q000628:therapy*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004734:Energy Metabolism; D005260:Female; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D007773:Lactates / Q000378:metabolism; D008751:Methylene Blue / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010101:Oxygen Consumption; D013329:Structure-Activity Relationship; D000077204:Temozolomide; D014048:Tolonium Chloride / Q000494:pharmacology
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D007773:Lactates; D014048:Tolonium Chloride; D003606:Dacarbazine; D000255:Adenosine Triphosphate; D008751:Methylene Blue; D000077204:Temozolomide