Molecular mechanism of diclofenac-induced apoptosis of promyelocytic leukemia: dependency on reactive oxygen species, akt, bid, cytochrome and caspase pathway

Autor: Hiroshi Tamai, Akiko Inoue, Tomoko Kanno, Kozo Utsumi, Hirofumi Fujita, Shikibu Muranaka
Rok vydání: 2004
Předmět:
Diclofenac
Morpholines
Antineoplastic Agents
Apoptosis
HL-60 Cells
DNA Fragmentation
Cysteine Proteinase Inhibitors
Protein Serine-Threonine Kinases
Biochemistry
Amino Acid Chloromethyl Ketones
chemistry.chemical_compound
Leukemia
Promyelocytic
Acute
Proto-Oncogene Proteins
Physiology (medical)
Cyclosporin a
Cyclic AMP
Humans
LY294002
Enzyme Inhibitors
Protein kinase B
Caspase
Phosphoinositide-3 Kinase Inhibitors
chemistry.chemical_classification
Reactive oxygen species
Estradiol
biology
Superoxide Dismutase
Cytochrome c
Anti-Inflammatory Agents
Non-Steroidal
Cytochromes c
Drug Synergism
DNA
Neoplasm
Molecular biology
2-Methoxyestradiol
Acetylcysteine
Enzyme Activation
chemistry
Chromones
Caspases
Cyclosporine
biology.protein
DNA fragmentation
Carrier Proteins
Reactive Oxygen Species
Oligopeptides
Proto-Oncogene Proteins c-akt
BH3 Interacting Domain Death Agonist Protein
Signal Transduction
Zdroj: Free Radical Biology and Medicine. 37:1290-1299
ISSN: 0891-5849
DOI: 10.1016/j.freeradbiomed.2004.07.003
Popis: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in a variety of cells, but the mechanism of this effect has not been fully elucidated. We report that diclofenac, a NSAID, induces growth inhibition and apoptosis of HL-60 cells through modulation of mitochondrial functions regulated by reactive oxygen species (ROS), Akt, caspase-8, and Bid. ROS generation occurs in an early stage of diclofenac-induced apoptosis preceding cytochrome c release, caspase activation, and DNA fragmentation. N-Acetyl-L-cysteine, an antioxidant, suppresses ROS generation, Akt inactivation, caspase-8 activation, and DNA fragmentation. Cyclic AMP, an inducer of Akt phosphorylation, suppresses Akt inactivation, Bid cleavage, and DNA fragmentation. LY294002, a PI3 kinase inhibitor, enhances Akt inactivation and DNA fragmentation. Ac-IETD-CHO, a caspase-8 inhibitor, suppresses Bid cleavage and DNA fragmentation. z-VAD-fmk, a universal caspase inhibitor, but not cyclosporin A (CsA), an inhibitor of mitochondrial membrane permeability transition, suppresses DNA fragmentation. These results suggest the sequential mechanism of diclofenac-induced apoptosis of HL-60 cells: ROS generation suppresses Akt activity, thereby activating caspase-8, which stimulates Bid cleavage and induces cytochrome c release and the activation of caspase-9 and-3 in a CsA-insensitive mechanism. Furthermore, we found that 2-methoxyestradiol (2-ME), a superoxide dismutase inhibitor, significantly enhances diclofenac-induced apoptosis; that is, diclofenac combined with 2-ME may have therapeutic potential in the treatment of human leukemia.
Databáze: OpenAIRE
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