title: Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors.
abstract: The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS) or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an "Achilles heel" for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations.
authors.affiliation: Department of Medical and Health Sciences, Linköping University, SE-581 83 Linköping, Sweden. Xiaonan.Zhang@ki.se.|Department of Oncology-Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden. Xiaonan.Zhang@ki.se.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden. Angelo.De-Milito@ki.se.
authors.forename: Angelo
authors.initials: A
authors.lastname: de Milito
authors.affiliation: Department of Oncology-Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden. Maria.Hagg@ki.se.
authors.forename: Maria Hägg
authors.initials: MH
authors.lastname: Olofsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Section of Oncology, Uppsala University, 751 85 Uppsala, Sweden. joachim.gullbo@medsci.uu.se.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
authors.affiliation: Department of Medical and Health Sciences, Linköping University, SE-581 83 Linköping, Sweden. padraig.darcy@liu.se.|Department of Oncology-Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden. padraig.darcy@liu.se.
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.affiliation: Department of Medical and Health Sciences, Linköping University, SE-581 83 Linköping, Sweden. Stig.Linder@ki.se.|Department of Oncology-Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden. Stig.Linder@ki.se.
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D005947:Glucose
keywords: cancer therapy; glucose; mitochondria; multicellular tumor spheroids; oxidative phosphorylation; solid tumor