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

Anticancer Res. 2002 Jan-Feb;22(1A):211-4.


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.

MeSH terms

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


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