title: Targeting the disturbed redox equilibrium in chronic lymphocytic leukemia by novel reactive oxygen species-catalytic 'sensor/effector' compounds.
abstract: Precursor transformation, clonal sustenance, and therapeutic resistance in cancer are significantly mediated by deregulated reactive oxygen species (ROS), which primarily act as DNA-stressors. Here, we demonstrate that elevated ROS in chronic lymphocytic leukemia (CLL) may represent a promising therapeutic target. We designed organochalcogens, which, based on a 'sensor/effector' principle, would confer selective cytotoxicity through the generation of intolerably high ROS levels preferentially in CLL cells, as these carry a high-level redox burden. Our novel compounds show an encouraging profile of efficient induction of apoptosis, low normal cell toxicity, and promising chemotherapy synergism. These findings warrant further mechanistic and preclinical studies of this therapeutic principle in CLL.
authors.affiliation: Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln Bonn, University of Cologne, Cologne, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Lilienthal
authors.forename: Christian
authors.initials: C
authors.lastname: Prinz
authors.forename: Abdul A
authors.initials: AA
authors.lastname: Peer-Zada
authors.forename: Mandy
authors.initials: M
authors.lastname: Doering
authors.forename: Lalla A
authors.initials: LA
authors.lastname: Ba
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.forename: Claus
authors.initials: C
authors.lastname: Jacob
authors.forename: Marco
authors.initials: M
authors.lastname: Herling
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002384:Catalysis; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D009930:Organic Chemicals / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D009930:Organic Chemicals; D017382:Reactive Oxygen Species; D014740:Vidarabine; D005978:Glutathione; C024352:fludarabine