Antitumour activity of S-p-bromobenzylglutathione cyclopentyl diester in vitro and in vivo. Inhibition of glyoxalase I and induction of apoptosis.

The glyoxalase I inhibitor diester, S-p-bromobenzyl-glutathione cyclopentyl diester (BrBzGSHCp2), inhibited the growth of human leukaemia 60 (HL60) cells in vitro. The median growth inhibitory concentration GC50 value of BrBzGSHCp2 was 4.23 +/- 0.001 microM (n = 21), and the median toxic concentration TC50 value was 8.86 +/- 0.01 microM (n = 21). BrBzGSHCp2 inhibited DNA synthesis in the third hr of incubation: the median inhibitory concentration IC50 value was 6.11 +/- 0.02 microM (n = 8). Incubation of HL60 cells with 10 microM BrBzGSHCp2 delivered the diester into cells: de-esterification of the diester there in lead to formation of the S-p-bromobenzylglutathione, inhibition of glyoxalase I activity in situ, increase in the methylglyoxal concentration after 1 hr, and induction of apoptosis after 6 hr. BrBzGSHCp2 (50-200 mg/kg) also inhibited the growth of murine adenocarcinoma 15A in vivo. Glyoxalase I inhibitor diesters may, therefore, inhibit tumour growth by inducing the accumulation of methylglyoxal in tumour cells, and induction of apoptosis.