ABSTRACT
Natural products from plants are expected to play significant roles in creating new, safe and improved chemopreventive and therapeutic antitumor agents. Selectivity is also an important issue in cancer prevention and therapy. The present study was designed to extend our previous study on the c-Ha-ras and c-myc-induced tumor cell-selective antiproliferative effects of a licorice component, glycyrrhetinic acid (GA). An in silico ligand-receptor docking simulation revealed that GA acts as an 11ß-hydroxysteroid dehydrogenase type 2 inhibitor. GA disrupted the redox balance in tumor cells through upregulation of reactive oxygen species and downregulation of glutathione (GSH). The GA-induced GSH reduction and cytotoxicity were enhanced by an inhibitor of GSH, l-buthionine-[S,R]-sulfoximine. N-acetyl-l-cysteine, an antioxidant and precursor of GSH, restored the GA-induced GSH reduction and cytotoxicity in tumor cells. Taken together, these data highlighting the downregulation of GSH by GA and the efficacy of GSH in ameliorating GA-mediated cytotoxicity support the notion that GSH is involved in the selective toxicity of GA toward tumor cells.
Subject(s)
Cell Proliferation/drug effects , Down-Regulation/drug effects , Glutathione/metabolism , Glycyrrhetinic Acid/pharmacology , 11-beta-Hydroxysteroid Dehydrogenase Type 2/antagonists & inhibitors , 11-beta-Hydroxysteroid Dehydrogenase Type 2/chemistry , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Acetylcysteine/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Buthionine Sulfoximine/pharmacology , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Dose-Response Relationship, Drug , Free Radical Scavengers/pharmacology , Glycyrrhetinic Acid/chemistry , Glycyrrhetinic Acid/metabolism , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , Neoplasms/metabolism , Neoplasms/pathology , Oxidation-Reduction/drug effects , Protein Binding , Protein Conformation , Reactive Oxygen Species/metabolism , Up-Regulation/drug effectsABSTRACT
Silk gland elongation factor 1 (EF-1) consists of four subunits: alpha, beta, beta', and gamma. EF-1 beta beta' gamma catalyzes the exchange of GDP for GTP on EF-1 alpha and stimulates the binding of EF-1 alpha-dependent aminoacyl-tRNA to ribosomes. The carboxy-terminal regions of the EF-1 beta subunits from various species are highly conserved. We examined the region of EF-1 beta' that binds to EF-1 alpha by in vitro binding assays, and examined the GDP/GTP exchange activity using deletion mutants of a GST-EF1 beta' fusion protein. We thereby suggested a pivotal amino acid region, residues 189-222, of EF-1 beta' for binding to EF-1 alpha.
