title: Effective elimination of cancer stem cells by a novel drug combination strategy.
abstract: Development of effective therapeutic strategies to eliminate cancer stem cells, which play a major role in drug resistance and disease recurrence, is critical to improve cancer treatment outcomes. Our study showed that glioblastoma stem cells (GSCs) exhibited low mitochondrial respiration and high glycolytic activity. These GSCs were highly resistant to standard drugs such as carmustine and temozolomide (TMZ), but showed high sensitivity to a glycolytic inhibitor 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), especially under hypoxic conditions. We further showed that combination of 3-BrOP with carmustine but not with TMZ achieved a striking synergistic effect and effectively killed GSCs through a rapid depletion of cellular ATP and inhibition of carmustine-induced DNA repair. This drug combination significantly impaired the sphere-forming ability of GSCs in vitro and tumor formation in vivo, leading to increase in the overall survival of mice bearing orthotopic inoculation of GSCs. Further mechanistic study showed that 3-BrOP and carmustine inhibited glyceraldehyde-3-phosphate dehydrogenase and caused a severe energy crisis in GSCs. Our study suggests that GSCs are highly glycolytic and that certain drug combination strategies can be used to effectively overcome their drug resistance based on their metabolic properties.
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Yuan
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Li
authors.forename: Rui-Hua
authors.initials: RH
authors.lastname: Xu
authors.forename: Jianping
authors.initials: J
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002330:Carmustine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D006842:Hydrocarbons, Brominated / Q000494:pharmacology*; D000860:Hypoxia; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D000077204:Temozolomide
chemical_list: C568307:3-bromo-2-oxopropionate-1-propyl ester; D004338:Drug Combinations; D006842:Hydrocarbons, Brominated; D011422:Propionates; D003606:Dacarbazine; D000255:Adenosine Triphosphate; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D002330:Carmustine; D000077204:Temozolomide