Inhibition of human leukaemia 60 cell growth by mercapturic acid metabolites of phenylethyl isothiocyanate.
Mercapturic acid pathway metabolites of phenylethyl isothiocyanate inhibited the growth of human leukaemia 60 (HL60) cells in vitro. The adduct with L-cysteine, S-(N-phenylethylthiocarbamoyl)cysteine, was the most potent with strong antileukaemic activity: the median growth inhibitory concentration (GC50) value was 336 +/- 1 nM (N = 18) compared with GC50 values of the precursor formed from dietary glucosinolates, phenylethyl isothiocyanate, 1.49 +/- 0.01 microM (N = 8), and the initial mercapturic acid pathway metabolite S-(N-phenylethylthiocarbamoyl)glutathione 5.46 +/- 0.36 microM (N = 18). S-(N-Benzylthiocarbamoyl)cysteine and S-(N-phenylpropylthiocarbamoyl)cysteine also had antiproliferative activity but S-(N-phenylethylthiocarbamoyl)cysteine was the most potent compound studied. The latter induced DNA fragmentation in HL60 cells but DNA laddering characteristic of apoptosis was not observed. It had low toxicity to corresponding differentiated cells, neutrophils, in culture, and therefore the cytotoxicity had selectivity for leukaemia cells. The antiproliferative activity of S-(N-phenylethylthiocarbamoyl)cysteine was lost during preincubation with culture medium, attributed to s-thiocarbamoyl transfer to serum proteins, which may decrease its effectiveness in vivo. The antiproliferative activity of S-(N-phenylalkylthiocarbamoyl)cysteine derivatives, by inhibiting tumour growth in pre-clinical development, may contribute to the association of decreased cancer incidence with dietary glucosinolate consumption.
Adesida
A
A
Department of Biological and Chemical Sciences, University of Essex, Colchester, UK.
Edwards
L G
LG
Thornalley
P J
PJ
D000111:Acetylcysteine / Q000378:metabolism* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D006801:Humans; D017953:Isocyanates / Q000378:metabolism* / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D017953:Isocyanates; C020790:phenylethyl isocyanate; D004247:DNA; D000111:Acetylcysteine