title: Iron chelators target both proliferating and quiescent cancer cells.
abstract: Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.affiliation: Department of Medical and Health Sciences, Linköping University, SE-58183 Linköping, Sweden.|Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Beactica, SE-754 50 Uppsala, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Bremberg
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Senkowski
authors.affiliation: Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
authors.forename: Maria Hägg
authors.initials: MH
authors.lastname: Olofsson
authors.affiliation: Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Brandt
authors.affiliation: Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences, P.O. Box 7015, SE-756 51 Uppsala, Sweden.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Persson
authors.affiliation: Department of Medical and Health Sciences, Linköping University, SE-58183 Linköping, Sweden.
authors.forename: Padraig
authors.initials: P
authors.lastname: D'Arcy
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-751 85 Uppsala, Sweden.|Department of Immunology, Genetics and Pathology, Section of Oncology, Uppsala University, SE-75185, Uppsala, Sweden.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
authors.affiliation: Department of Immunology, Genetics and Pathology, Section of Oncology, Uppsala University, SE-75185, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Nygren
authors.affiliation: OncoRay-National Center for Radiation Research in Oncology, TU Dresden, D-01307 Dresden, Germany.
authors.forename: Leoni Kunz
authors.initials: LK
authors.lastname: Schughart
authors.affiliation: Department of Medical and Health Sciences, Linköping University, SE-58183 Linköping, Sweden.|Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, SE-171 76 Stockholm, Sweden.
authors.forename: Stig
authors.initials: S
authors.lastname: Linder
authors.affiliation: Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D007502:Iron Chelating Agents; D014230:Triazoles; C000602558:VLX600; D012264:Ribonucleotide Reductases; D003676:Deferoxamine