INHIBITION OF HUMAN-LEUKEMIA-60 CELL-GROWTH BY MERCAPTURIC ACID METABOLITES OF PHENYLETHYL ISOTHIOCYANATE

Mercapturic acid pathway metabolites of phenylethyl isothiocyanate inh ibited the growth of human leukaemia 60 (HL60) cells in vitro. The add uct with L-cysteine, S-(N-phenylethylthiocarbamoyl)cysteine, was the m ost potent with strong antileukaemic activity: the median growth inhib itory concentration (GC(50)) value was 336 +/- 1 nM (N = 18) compared with GC(50) values of the precursor formed from dietary glucosinolates , phenylethyl isothiocyanate, 1.49 +/- 0.01 mu M (N = 8), and the init ial mercapturic acid pathway metabolite S-(N-phenylethylthiocarbamoyl) glutathion 5.46 +/- 0.36 mu M (N = 18). S-(N-Benzylthiocarbamoyl)cyste ine and S-(N-phenylpropylthiocarbamoyl)cysteine also had antiprolifera tive 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 leuka emia cells. The antiproliferative activity of S-(N-phenylethylthiocarb amoyl)cysteine was lost during preincubation with culture medium, attr ibuted to S-thiocarbamoyl transfer to serum proteins, which may decrea se its effectiveness in vivo. The antiproliferative activity of S-(N-p henylalkylthiocarbamoyl)cysteine derivatives, by inhibiting tumour gro wth in pre-clinical development, may contribute to the association of decreased cancer incidence with dietary glucosinolate consumption. (C) 1996 Elsevier Science Ltd. All rights reserved.