Comparison of in vitro cytotoxicity of N-acetyl and N-propionyl derivatives of phenolic thioether amines in melanoma and neuroblastoma cells and the relationship to tyrosinase and tyrosine hydroxylase enzyme activity

Our laboratory has synthesized two new phenolic thioether amines, N-propion yl-4-S-cysteaminylphenol (N-Pr-4-S-CAP) and N-[2-{(4-propionyloxyphenyl)thi o}ethyl] propionamide (N,O-diPr-4-S-CAP). These compounds, along with the p reviously described phenolic thioether amine N-acetyl-4-S-cysteaminylphenol (N-Ac-4-S-CAP) and its acetyl form (N,O-diAc-4-S-CAP), are tyrosine-amine derivative analogues. The cytotoxicity of these compounds is thought to be tyrosinase dependent, which may make them suitable for targeted anti-melano ma therapy since only melanocytes and their malignant counterparts contain this active enzyme. To further investigate this hypothesis, we performed MT T [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide] assays to d etermine the cytotoxicity of these compounds in 10 different cell lines. sp ecifically, we examined to what extent cytotoxicity is related to tyrosinas e and tyrosine hydroxylase activity using melanoma and neuroblastoma cells, which have a common metabolic pathway using tyrosinase and tyrosine hydrox ylase, respectively. The most sensitive cell line was the highly pigmented SK-MEL-23 melanoma cell line, which shows a very high tyrosinase activity w ith the highest melanin pigmentation. KAN and SK-NSH (two neuroblastoma cel l lines), which have no tyrosinase activity but high tyrosine hydroxylase, were also sensitive. However, C32 (a nonpigmented melanoma with a lower tyr osinase activity) was also sensitive, and MeWo (a moderately pigmented mela noma with a high tyrosinase activity) was less sensitive. This in vitro stu dy may indicate that there is a non-tyrosinase-mediated mechanism of cytoto xicity for phenolic thioether amines in addition to the tyrosinase-mediated one described previously. (C) 2000 Lippincott Williams & Wilkins.