title: Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism.
abstract: Because radiotherapy significantly increases median survival in patients with glioblastoma, the modulation of radiation resistance is of significant interest. High glycolytic states of tumor cells are known to correlate strongly with radioresistance; thus, the concept of metabolic targeting needs to be investigated in combination with radiotherapy. Metabolically, the elevated glycolysis in glioblastoma cells was observed postradiotherapy together with upregulated hypoxia-inducible factor (HIF)-1α and its target pyruvate dehydrogenase kinase 1 (PDK1). Dichloroacetate, a PDK inhibitor currently being used to treat lactic acidosis, can modify tumor metabolism by activating mitochondrial activity to force glycolytic tumor cells into oxidative phosphorylation. Dichloroacetate alone demonstrated modest antitumor effects in both in vitro and in vivo models of glioblastoma and has the ability to reverse the radiotherapy-induced glycolytic shift when given in combination. In vitro, an enhanced inhibition of clonogenicity of a panel of glioblastoma cells was observed when dichloroacetate was combined with radiotherapy. Further mechanistic investigation revealed that dichloroacetate sensitized glioblastoma cells to radiotherapy by inducing the cell-cycle arrest at the G2-M phase, reducing mitochondrial reserve capacity, and increasing the oxidative stress as well as DNA damage in glioblastoma cells together with radiotherapy. In vivo, the combinatorial treatment of dichloroacetate and radiotherapy improved the survival of orthotopic glioblastoma-bearing mice. In conclusion, this study provides the proof of concept that dichloroacetate can effectively sensitize glioblastoma cells to radiotherapy by modulating the metabolic state of tumor cells. These findings warrant further evaluation of the combination of dichloroacetate and radiotherapy in clinical trials.
authors.affiliation: Cure Brain Cancer Neuro-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Han
authors.initials: H
authors.lastname: Shen
authors.affiliation: Cure Brain Cancer Neuro-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia. Cancer Care Centre, St George Hospital, Kogarah, New South Wales, Australia.
authors.forename: Eric
authors.initials: E
authors.lastname: Hau
authors.affiliation: Cure Brain Cancer Neuro-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Swapna
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Tumour Metabolism Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Dilda
authors.affiliation: Cure Brain Cancer Neuro-Oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia. k.mcdonald@unsw.edu.au.
authors.forename: Kerrie L
authors.initials: KL
authors.lastname: McDonald
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000528:radiation effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003999:Dichloroacetic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000528:radiation effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010641:Phenotype; D011836:Radiation Tolerance; D011878:Radiotherapy; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; D003999:Dichloroacetic Acid; D005947:Glucose