title: Induction of non-apoptotic cell death by morphinone in human promyelocytic leukemia HL-60 cells.
abstract: As previously suggested, codeinone (oxidation product of codeine) induces non-apoptotic cell death, characterized by marginal caspase activation and the lack of DNA fragmentation in HL-60 human promyelocytic leukemia cells, which was inhibited by N-acetyl-L-cysteine. Whether, morphinone, an oxidative metabolite of morphine, also induced a similar type of cell death in HL-60 cells was investigated. Morphinone showed slightly higher cytotoxic activity against human tumor cell lines (oral squamous cell carcinoma HSC-2, HSC-3, HSC-4, NA, Ca9-22, promyelocytic leukemia HL-60, cervical carcinoma HeLa) than against normal oral human cells (gingival fibroblast HGF, pulp cells HPC, periodontal ligament fibroblast HPLF). Morphinone also induced an almost undetectable level of internucleosomal DNA fragmentation in the HL-60 cells. Morphinone did not activate caspase-8 or -9 in these cells. Morphinone dose-dependently activated caspase-3 in both HL-60 and HSC-2 cell lines, but to a much lesser extent than actinomycin D. Electron microscopy demonstrated that morphinone induced mitochondrial shrinkage, vacuolization and production of autophagosome and the loss of cell surface microvilli, without destruction of cell surface and nuclear membranes in the HL-60 cells. The autophagy inhibitor 3-methyladenine (0.3-10 mM) slightly inhibited the morphinone-induced cytotoxicity, when corrected for its own cytotoxicity. These data suggest that morphinone induces non-apoptotic cell death in HL-60 cells.
authors.affiliation: Division of Anesthesiology, Department of Comprehensive Medical Sciences, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Takeuchi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hoshijima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagasaka
authors.forename: Shahead Ali
authors.initials: SA
authors.lastname: Chowdhury
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kanda
authors.forename: Shiro
authors.initials: S
authors.lastname: Kunii
authors.forename: Masami
authors.initials: M
authors.lastname: Kawase
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D004091:Hydromorphone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*
chemical_list: D003609:Dactinomycin; C036083:morphinone; D053148:Caspase 3; D053181:Caspase 8; D004091:Hydromorphone