Selective toxicity of glycyrrhetinic acid against tumorigenic r/m HM-SFME-1 cells is potentially attributed to downregulation of glutathione

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 11β-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.

The proposed mechanism underlying the GA-induced tumor-cell selective toxicity. Various tumor cells exhibit higher 11βHSD2 expression, which suggests that the metabolic cascades through 11βHSD2 could be relatively easily triggered and this may make the tumor cells sensitive to 11βHSD2 inhibition. Previous studies have revealed that GA, an 11βHSD2 inhibitor, is toxic against tumor cells. Our present in silico study shows that GA acts as a competitive inhibitor of 11βHSD2. GA upregulates ROS and downregulates GSH, and consequently induces tumor-cell selective toxicity.Figure optionsDownload high-quality image (57 K)Download as PowerPoint slideHighlights
► An in silico docking simulation reveals that GA acts as an 11βHSD2 inhibitor.
► GA disrupts the redox balance in tumor cells through ROS increase and GSH decrease.
► The GA-induced GSH reduction and cytotoxicity are enhanced by a GSH inhibitor, BSO.
► NAC restores the GA-induced GSH reduction and cytotoxicity in tumor cells.