Cell death-inducing activity of opiates in human oral tumor cell lines.
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.
Kawase
Masami
M
Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan. kawasema@josai.ac.jp
Sakagami
Hiroshi
H
Furuya
Kenichiro
K
Kikuchi
Hirotaka
H
Nishikawa
Hirofumi
H
Motohashi
Noboru
N
Morimoto
Yasunori
Y
Varga
Andreas
A
Molnár
Joseph
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002648:Child; D003061:Codeine / Q000031:analogs & derivatives* / Q000633:toxicity; D018432:Drug Resistance, Multiple; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005881:Gingiva / Q000166:cytology; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007940:Leukemia L5178 / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009022:Morphine Derivatives / Q000633:toxicity*; D012468:Salivary Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009022:Morphine Derivatives; C046414:6-codeinone; D003061:Codeine