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.