Induction of apoptosis by anesthetics in the human cancer cell lines.

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There are relatively few studies about antiproliferative effects of codeinone-related compounds on human cancer cell lines, compared with those of morphine related compounds. The authors previously found that codeinone, an oxidation metabolite of codeine, among 10 opiois, showed the highest cytotoxic activity (DNA fragmentation-inducing activity) agains human promyelocytic leukemic cell lines (HL-60). This was counteracted by an antioxidant, N-acetyl-L-cysteine (NAC). These finings prompted us performed a more detailed study of apoptosis induction after codeinone treatment. Apoptosis was induced by treating HL60 cells for 1-6h with codeine or codeinone. DNA after staining with diamidinopheylindole (DAPI). The appearance of apoptotic cells was monitored bymicroscopic observation after staining with Hoechst (H)-33342,and fluorescence actiated cell sorter (FACS) after staining with Annexin. The release of cytochrome C and cytocrome oxidase from mitochondria and activation of caspase 3 were monitored by Western blot analysis. Intracellular caspase 3 like activity was confirmed by FACS, using cell permeable substate. Mitochondrial manganese-containing superoxide dismutase (MnSOD) activity and mRNAexpression were assayed by ativity staining after separation on the polyacrylamide gel electrophoresis, and reverse transcriptase-poly-merase chain reaction (RT-PCR), respectively. Codeinone induced internucleosomal DNA fragmentation and production of Annexin-positive apoptotic cells more potently than codeine in HL-60 cells. Codeinone stimulated the release of both cytochrome C and cytochrome oxidase, and cleavage of procaspase 3 without significant changes in both the activity and expression of MnSOD. Codeinone was found to possess both apoptosis and necrosis-inducing activity, in addition to the reported antinociceptive activity, further substantiated its antitumor potential.