title: Isofraxidin, a potent reactive oxygen species (ROS) scavenger, protects human leukemia cells from radiation-induced apoptosis via ROS/mitochondria pathway in p53-independent manner.
abstract: Ionizing radiation (IR) leads to oxidizing events such as excessive reactive oxygen species (ROS) in the exposed cells, resulting in further oxidative damage to lipids, proteins and DNA. To screen the potential radio-protective drug, the intracellular ROS was measured in irradiated U937 cells pretreated with 80 candidate traditional herbal medicine, respectively. Isofraxidin (IF) was one possible radio-protector in these 80 drugs. This study investigated the radio-protective role of IF, a Coumarin compound, in human leukemia cell lines, for the first time. Results indicate that IF protects against IR-induced apoptosis in U937 cells in the time- and concentration- dependent manner. IF decreases IR-induced intracellular ROS generation, especially hydroxyl radicals formation, inhibits IR-induced mitochondrial membrane potential loss and reduces IR-induced high intracellular Ca(2+) levels regardless of ER stress. IF down-regulates the expression of caspase-3, phospho-JNK, phospho-p38 and activates Bax in mitochondria. IF inhibits cytochrome c release from mitochondria to cytosol. IF also moderates IR-induced Fas externalization and caspase-8 activation. IF also exhibits significant protection against IR-induced cell death in other leukemia cell lines such as Molt-4 cells and HL60 cells regardless of p53. Taken together, the data demonstrate that IF protects leukemia cells from radiation-induced apoptosis via ROS/mitochondria pathway in a p53-independent manner.
authors.affiliation: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: Zhao
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Wu
authors.forename: Paras
authors.initials: P
authors.lastname: Jawaid
authors.forename: Yu-Fei
authors.initials: YF
authors.lastname: Jiao
authors.forename: Makoto
authors.initials: M
authors.lastname: Kadowaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Kondo
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia; D008223:Lymphoma; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D011837:Radiation-Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014965:X-Rays
chemical_list: D003374:Coumarins; D016166:Free Radical Scavengers; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C008182:isofraxidin