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Cell death-inducing activity of opiates in human oral tumor cell lines
Masami Kawase1, Hiroshi Sakagami, Kenichiro Furuya
1Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan. kawasema@josai.ac.jp
Abstract:
In screening cytotoxic agents in morphine alkaloids [TE1-10], codeinone [TE8] was cytotoxic against two human oral tumor cells lines (HSC-2 and HSG). The cytotoxic activity of codeinone (CC50=1.0-1.2 microg/mL) against HSC-2 or HSG cells was higher than that of doxorubicin (CC50=1.9-2.0 microg/mL). Human oral gingival fibroblasts (HGF) were relatively resistant to codeinone, as judged by higher SI ratio (3.7) suggesting the tumor-selective cytotoxicity of codeinone. The cytotoxic activity of morphine (CC50=221 microg/mL) against HSC-2 was slightly lower than that of codeine (CC50=186 microg/mL), thebaine (CC50=125 microg/mL), etorphine (CC50=94 microg/mL) or dihydroetorphine (CC50=60 microg/mL). A study of structurally-related compounds suggested that the alpha,beta-unsaturated ketone group of codeinone was responsible for its antitumor cytotoxicity. The cytotoxic activity of codeinone was significantly reduced by N-acetylcysteine, but not affected by FeCl3, CuCl2, CoCl2, sodium ascorbate or catalase. Neither codeinone nor morphine inhibited P-glycoprotein-mediated rhodamine-123 efflux in multidrug resistant mouse T lymphoma L5178 transfected with human MDR 1 gene. These data suggest that codeinone induces cytotoxicity in oral tumor cell lines, possibly by a Michael-like addition of a protein SH or of an amino group to the bouble bond of codeinone.
Insights
Codeinone exhibits potent anti-cancer activity against oral tumor cells, surpassing doxorubicin in efficacy. Its tumor-selective cytotoxicity suggests potential as a novel therapeutic agent for oral cancers.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Oncology
Background:
- Morphine alkaloids are being screened for cytotoxic agents.
- Codeinone was identified as a promising cytotoxic compound.
Purpose of the Study:
- To evaluate the cytotoxic activity of codeinone against oral tumor cell lines.
- To investigate the mechanism of codeinone's antitumor cytotoxicity.
Main Methods:
- Cytotoxicity assays were performed on human oral tumor cell lines (HSC-2, HSG) and human oral gingival fibroblasts (HGF).
- Structurally related compounds were analyzed to identify key functional groups responsible for cytotoxicity.
- The effect of various chemical agents (N-acetylcysteine, metal chlorides, etc.) and P-glycoprotein inhibition was assessed.
Main Results:
- Codeinone demonstrated significant cytotoxicity against HSC-2 and HSG cells (CC50=1.0-1.2 µg/mL), exceeding that of doxorubicin.
- Codeinone exhibited tumor-selective cytotoxicity with a higher safety margin in normal fibroblasts (SI ratio=3.7).
- The alpha,beta-unsaturated ketone group in codeinone was identified as crucial for its antitumor activity, potentially acting via Michael-like addition.
Conclusions:
- Codeinone possesses potent and tumor-selective cytotoxic activity against oral cancer cell lines.
- The mechanism likely involves a Michael-like addition reaction with cellular nucleophiles.
- Codeinone represents a potential lead compound for the development of novel oral cancer therapeutics.