title: Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells.
abstract: We investigated whether altering Warburg metabolism (aerobic glycolysis) by treatment with the metabolic agent dichloroacetate (DCA) could increase the X-ray-induced cell killing of the radiation-resistant human non-small-cell lung cancer (NSCLC) cell lines A549 and H1299. Treatment with 50mM DCA decreased lactate production and glucose consumption in both A549 and H1299, clear indications of attenuated aerobic glycolysis. In addition, we found that DCA treatment also slowed cell growth, increased population-doubling time, and altered cell cycle distribution. Furthermore, we report that treatment with 50mM DCA significantly increased single and fractionated X-ray-induced cell killing of A549 and H1299 cells. Assay of DNA double-strand break repair by neutral comet assays demonstrated that DCA inhibited both the fast and the slow kinetics of X-ray-induced DSB repair in both A549 and H1299 NSCL cancer cells. Taken together the data suggest a correlation between an attenuated aerobic glycolysis and enhanced cytotoxicity and radiation-induced cell killing in radiation-resistant NSCLC cells.
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: Kah Tan
authors.initials: KT
authors.lastname: Allen
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Chin-Sinex
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: DeLuca
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Pomerening
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sherer
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Watkins
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA; Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: John
authors.initials: J
authors.lastname: Foley
authors.affiliation: Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47405, USA.
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Jesseph
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: mmendonc@iupui.edu.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Mendonca
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014965:X-Rays
chemical_list: D003999:Dichloroacetic Acid
keywords: Dichloroacetate (DCA); Double-strand DNA break repair; Fractionated/split-dose; Non-small cell lung cancer (NSCLC); Warburg effect