Abstract | BACKGROUND: There are relatively few studies about the antiproliferative effects of codeine-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 opioids, showed the highest cytotoxic activity (DNA fragmentation-inducing activity) against human promyelocytic leukemic cell lines (HL-60). This was counteracted by an antioxidant, N-acetyl-L-cysteine (NAC). These findings prompted us to perform a more detailed study of apoptosis induction after codeinone treatment. METHODS: Apoptosis was induced by treating HL-60 cells for 1-6 h with codeine or codeinone. DNA fragmentation was assessed by both agarose gel electrophoresis and fluorometric determination of the fragmented DNA after staining with diamidinophenylindole ( DAPI). The appearance of apoptotic cells was monitored by microscopic observation after staining with Hoechst (H)-33342, and fluorescence activated cell sorter (FACS) after staining with Annexin. The release of cytochrome c and cytochrome 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 substrate. Mitochondrial manganese-containing superoxide dismutase (MnSOD) activity and mRNA expression were assayed by activity staining after separation on the polyacrylamide gel electrophoresis, and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. RESULTS: CONCLUSIONS:
Codeinone was found to possess both apoptosis and necrosis-inducing activity, in addition to the reported antinociceptive activity, further substantiating its antitumor potential.
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Authors | Naoko Hitosugi, Ikusuke Hatsukari, Rie Ohno, Ken Hashimoto, Saori Mihara, Satoshi Mizukami, Shinichi Nakamura, Hiroshi Sakagami, Hiroshi Nagasaka, Isao Matsumoto, Masami Kawase |
Journal | Anesthesiology
(Anesthesiology)
Vol. 98
Issue 3
Pg. 643-50
(Mar 2003)
ISSN: 0003-3022 [Print] United States |
PMID | 12606908
(Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Analgesics, Opioid
- Cytochrome c Group
- RNA, Messenger
- 6-codeinone
- Superoxide Dismutase
- CASP3 protein, human
- Caspase 3
- Caspases
- Codeine
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Topics |
- Analgesics, Opioid
(pharmacology)
- Apoptosis
(drug effects)
- Caspase 3
- Caspases
(metabolism)
- Codeine
(analogs & derivatives, blood, pharmacology)
- Cytochrome c Group
(metabolism)
- Dose-Response Relationship, Drug
- HL-60 Cells
- Humans
- RNA, Messenger
(analysis)
- Superoxide Dismutase
(genetics, metabolism)
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