Cell death-inducing activity of opiates in human oral tumor cell lines.

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.

• Authors: Masami Kawase, Hiroshi Sakagami, Kenichiro Furuya, Hirotaka Kikuchi, Hirofumi Nishikawa, Noboru Motohashi, Yasunori Morimoto, Andreas Varga, Joseph Molnár
• Journal: Anticancer research (Anticancer Res) 2002 Jan-Feb Vol. 22 Issue 1A Pg. 211-4 ISSN: 0250-7005 [Print] Greece
• PMID: 12017290 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Morphine Derivatives
• 6-codeinone
• Codeine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis, genetics)
• Animals
• Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
• Cell Death (drug effects)
• Child
• Codeine (analogs & derivatives, toxicity)
• Drug Resistance, Multiple
• Female
• Fibroblasts (cytology, drug effects, metabolism)
• Gingiva (cytology)
• HL-60 Cells (cytology, drug effects, metabolism)
• Humans
• Leukemia L5178 (drug therapy, genetics, metabolism, pathology)
• Mice
• Morphine Derivatives (toxicity)
• Salivary Gland Neoplasms (drug therapy, metabolism, pathology)
• Structure-Activity Relationship
• Transfection