title: Cytotoxicity of a selected series of substituted phenols towards cultured melanoma cells.
abstract: Substituted phenolic compounds were previously shown to exhibit cytotoxicity towards epithelial cells in the presence of the enzyme tyrosinase as a result of the formation of their quinone products. Seventeen of these compounds were tested for cytotoxic properties towards three different melanoma cell lines. The compounds were split into four groups of phenol derivatives, A; alkoxyethers, including 4-hydroxyanisole (4HA), B; oxyethers derivatized at the acyl side chain, C; oxyethers derivatized at the phenol, and D; acyl thioethers. Toxicity was determined by total cell counts after 3 days exposure to the compounds. Large reductions in cell numbers were observed with 4HA (the methoxy-), ethoxy-, propoxy and iso-butoxyethers of group A and the methyl- and propyl thioethers of phenol of group D. Derivatization of the ethoxy- and propoxy side chains (group B) did not seem to increase the cytotoxic effects, as determined by cell counts. Compounds of group C, which need intracellular esterase activity to release the phenols, showed moderate toxicities. Toxicity of certain compounds was confirmed by LDH release into the culture medium and by increased trypan blue uptake of cells exposed to the compounds. Flow cytometric investigations of cells after exposure for 24 h revealed that most compounds caused an increase in the proportion of cells in G1 phase. A complete accumulation of cells in S-phase was observed after exposure to 4-ethoxyphenol. Inhibition of DNA synthesis was also shown by inhibition of bromodeoxyuridine incorporation. The results presented show that phenolic compounds exhibit cytotoxic properties towards melanoma cells some of which may be mediated by tyrosinase activity. Toxicity of the compounds was shown to be exerted during DNA replication but their toxic action may also be due to membrane damage and inhibition of cell metabolism.
authors.affiliation: University of Amsterdam, Department of Dermatology, The Netherlands.
authors.forename: N P
authors.initials: NP
authors.lastname: Smit
authors.forename: K
authors.initials: K
authors.lastname: Peters
authors.forename: W
authors.initials: W
authors.lastname: Menko
authors.forename: W
authors.initials: W
authors.lastname: Westerhof
authors.forename: S
authors.initials: S
authors.lastname: Pavel
authors.forename: P A
authors.initials: PA
authors.lastname: Riley
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001973:Bromodeoxyuridine; D002470:Cell Survival / Q000187:drug effects*; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008545:Melanoma; D010636:Phenols / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D010636:Phenols; D007770:L-Lactate Dehydrogenase; D001973:Bromodeoxyuridine