title: Caspase-independent necrotic cell death induced by a radiosensitizer, 8-nitrocaffeine.
abstract: Molecular mechanisms of apoptosis have been extensively studied, but little is known about non-apoptotic cell death. To study the mechanism of non-apoptotic cell death, we searched for non-apoptotic cell death inducers for U937 cells, which are highly sensitive to apoptosis induction by various stimuli. We found that 8-nitrocaffeine and its analog, which are candidate radiosensitizers for cancer therapy, induced exclusively caspase-independent necrotic cell death in cell lines such as U937, HL-60, K562 and Jurkat. The 8-nitrocaffeine-induced necrotic cell death was mediated by reactive oxygen species (ROS) because (i) ROS were produced in the 8-nitrocaffeine-treated cells, (ii) ROS scavengers inhibited the caspase-independent necrotic cell death induced by 8-nitrocaffeine, and (iii) the necrotic cell death was completely suppressed in hypoxic cells. Cells selected for resistance to nitrocaffeine showed cross resistance to CH-11, an anti-Fas antibody, suggesting that the necrotic process plays an important role in Fas-mediated cell death in this cell line. Since cancer cells are often derived from a selected population of cells resistant to apoptosis, inducers of necrotic cell death could be beneficial to kill cancer cells that have acquired resistance to apoptosis-induction therapy.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan. mnaito@iam.u-tokyo.ac.jp
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
authors.forename: Chizuko
authors.initials: C
authors.lastname: Hashimoto
authors.forename: Shigeki
authors.initials: S
authors.lastname: Masui
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsuruo
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000968:Antimycin A / Q000494:pharmacology; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology*; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000187:drug effects*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000494:pharmacology; D005354:Fibrosarcoma / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells / Q000166:cytology / Q000187:drug effects; D020014:K562 Cells / Q000166:cytology / Q000187:drug effects; D009336:Necrosis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020298:U937 Cells / Q000166:cytology / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology / Q000502:physiology
chemical_list: C487642:1,7-dimethyl-8-nitroxanthine; C485124:8-nitrocaffeine; D000911:Antibodies, Monoclonal; D015853:Cysteine Proteinase Inhibitors; D016166:Free Radical Scavengers; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D014970:Xanthines; D019014:fas Receptor; D002110:Caffeine; D000968:Antimycin A; D005047:Etoposide; D020169:Caspases