title: Antitumour activity of S-p-bromobenzylglutathione cyclopentyl diester in vitro and in vivo. Inhibition of glyoxalase I and induction of apoptosis.
abstract: 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.
authors.affiliation: Department of Biological and Chemical Sciences, Central Campus, University of Essex, U.K.
authors.forename: P J
authors.initials: PJ
authors.lastname: Thornalley
authors.forename: L G
authors.initials: LG
authors.lastname: Edwards
authors.forename: Y
authors.initials: Y
authors.lastname: Kang
authors.forename: C
authors.initials: C
authors.lastname: Wyatt
authors.forename: N
authors.initials: N
authors.lastname: Davies
authors.forename: M J
authors.initials: MJ
authors.lastname: Ladan
authors.forename: J
authors.initials: J
authors.lastname: Double
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis; D002452:Cell Count / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007938:Leukemia / Q000188:drug therapy; D051379:Mice
chemical_list: D004952:Esters; C099177:S-4-bromobenzylglutathione cyclopentyl diester; D005978:Glutathione