9-deoxy-9-10-didehydro-12-13-didehydro-13-14-dihydroprostaglandin-d2 and Carcinoma--Hepatocellular

We studied the effect of intracellular glutathione (GSH), which was known to conjugate readily with an alpha, beta-unsaturated carbonyl of 9-deoxy-delta 9,12-13,14-dihydroPGD2 (delta 12-PGJ2), on the cytotoxicity of delta 12-PGJ2. delta 12-PGJ2 caused DNA fragmentation in human hepatocellular carcinoma Hep 3B cells, which was blocked by cycloheximide (CHX). The delta 12-PGJ2-induced apoptosis was augmented by GSH depletion resulted from pretreatment with buthioninine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. On the contrary, N-acetyl-cysteine (NAC), a precursor of cysteine, elevated the GSH level and protected cells from initiating apoptosis by delta 12-PGJ2. Sodium arsenite, a thiol-reactive agent, also induced apoptosis, which was potentiated or attenuated by BSO or NAC treatment respectively. These results suggest that the apoptosis-inducing activity of delta 12-PGJ2 is due to thiol-reactivity and intracellular GSH modulates the delta 12-PGJ2-induced apoptosis by regulating the accessibility of delta 12-PGJ2 to target proteins containing thiol groups.

Topics: Acetylcysteine; Antineoplastic Agents; Apoptosis; Arsenites; Buthionine Sulfoximine; Carcinoma, Hepatocellular; Cell Division; Cycloheximide; DNA Fragmentation; Electrophoresis, Agar Gel; Enzyme Inhibitors; Glutathione; Humans; Liver Neoplasms; Prostaglandin D2; Sodium Compounds; Structure-Activity Relationship; Sulfhydryl Compounds; Tumor Cells, Cultured