P-Terphenyl Derivatives from the Mushroom Thelephora aurantiotincta Suppress the Proliferation of Human Hepatocellular Carcinoma Cells via Iron Chelation

Abstract

A novel 2',3'-dihydroxy-p-terphenyl derivative, thelephantin O (TO), which has cancer-selective cytotoxicity, was isolated. This study investigated the underlying basis of the cytotoxicity of 2',3'-dihydroxy-p-terphenyl compounds in view of their ability to chelate metal ions. FeCl(2) significantly reduced TO-induced cytotoxicity, whereas several other salts of transition metals and alkaline-earth metals did not. A structure-activity relationship study using newly synthesized p-terphenyl derivatives revealed that o-dihydroxy substitution of the central benzene ring was necessary for both the cytotoxicity and Fe(2+) chelation of the compounds. Real-time PCR array and cell cycle analysis revealed that the TO-induced cytotoxicity was attributed to cell cycle arrest at the G1 phase via well-known cell cycle-mediated genes. The TO-induced changes in the cell cycle and gene expression were completely reversed by the addition of FeCl(2). Thus, it was concluded that Fe(2+) chelation occurs upstream in the pivotal pathway of 2',3'-dihydroxy-p-terphenyl-induced inhibition of cancer cell proliferation.