Inhibition of human leukaemia 60 cell growth by S-D-lactoylglutathione in vitro. Mediation by metabolism to N-D-lactoylcysteine and induction of apoptosis.
The inhibition of human leukaemia 60 cell growth by S-D-lactoylglutathione in vitro is mediated by the inhibtion of de novo pyridimine synthesis. When S-D-lactoylglutathione was added to human leukaemia 60 cells in culture, it was hydrolysed by thiolesterase activity to reduced glutathione and D-lactate but also converted to N-D-lactoylcysteinylglycine and N-D-lactoylcysteine by gamma-glutamyl transferase and dipeptidase. The N-D-lactoylcysteine inhibited human leukaemia 60 cell growth: the median growth inhibitory concentration IC(50) value was 46.7 +/ -0.9 (N=30) and the median toxic concentration TC(50) value was 103 +/- 1 microM. Other N-(R)2-hydroxyacylcysteine derivatives, N-D-mandelylcysteine and N-L-glyceroylcysteine, were less effective inhibitors of human leukaemia 60 cell growth, whereas N-D-lactoylcysteine ethyl ester was more effective: the IC(50) value was 16.5 +/- 1.5 microM(N=8). Cytotoxic concentrations of S-D-lactoylglutathione-induced apoptosis in human leukaemia 60 cells. The S-D-lactoylglutathione was not toxic to peripheral human lymphocytes at the same concentrations but rather induced growth arrest. The expected mechanism of action of N-D-lactoylcysteine is inhibition of dihydro-orotase, which is particularly susceptible to inhibition by cysteine derivatives.
Edwards
L G
LG
Department of Biological and Chemical Sciences, University of Essex, UK.
Adesida
A
A
Thornalley
P J
PJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003545:Cysteine / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans
D000970:Antineoplastic Agents; D005978:Glutathione; C013585:S-lactoylglutathione; D003545:Cysteine