title: Mitochondrial dysfunction in gliomas.
abstract: Mitochondrial (mt) dysfunction in gliomas has been linked to abnormalities of mt energy metabolism, marked by a metabolic shift from oxidative phosphorylation to glycolysis ("Warburg effect"), disturbances in mt membrane potential regulation and apoptotic signaling, as well as to somatic mutations involving the Krebs cycle enzyme isocitrate dehydrogenase. Evolving biological concepts with potential therapeutic implications include interaction between microtubule proteins and mitochondria (mt) in the control of closure of voltage-dependent anion channels and in the regulation of mt dynamics and the mt-endoplasmic reticulum network. The cytoskeletal protein βIII-tubulin, which is overexpressed in malignant gliomas, has emerged as a prosurvival factor associated in part with mt and also as a marker of chemoresistance. Mt-targeted therapeutic strategies that are discussed include the following: (1) metabolic modulation with emphasis on dichloroacetate, a pyruvate dehydrogenase kinase inhibitor; (2) tumor cell death via apoptosis induced by tricyclic antidepressants, microtubule-modulating drugs, and small molecules or compounds capable of inflicting reactive oxygen species-dependent tumor cell death; and (3) pretreatment mt priming and mt-targeted prodrug cancer therapy.
authors: Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA; Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, PA; Department of Neurology, Drexel University College of Medicine, Philadelphia, PA; Section of Neurology, St. Christopher's Hospital for Children, Philadelphia, PA. Electronic address: Christos.Katsetos@drexelmed.edu.
authors: Christos D
authors: CD
authors: Katsetos
authors: Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA.
authors: Helen
authors: H
authors: Anni
authors: Laboratory of the Biology of Cytoskeleton, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors: Pavel
authors: P
authors: Dráber
mesh_terms: D004721:Endoplasmic Reticulum / Q000378:metabolism; D005910:Glioma / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation