Novel Ferrocene Derivatives Induce G0/G1 Cell Cycle Arrest and Apoptosis through the Mitochondrial Pathway in Human Hepatocellular Carcinoma

Abstract

In this study, detailed information on hepatocellular carcinoma (HCC) cells (HepG-2, SMMC-7721, and HuH-7) and normal human liver cell L02 treated by ferrocene derivatives (compounds <b>1</b>, <b>2</b> and <b>3</b>) is provided. The cell viability assay showed that compound <b>1</b> presented the most potent and selective anti-HCC activity. Further mechanism study indicated that the proliferation inhibition effect of compound <b>1</b> was associated with the cycle arrest at the G0/G1 phase and downregulation of cyclin D1/CDK4. Moreover, compound <b>1</b> could induce apoptosis in HCC cells by loss of mitochondrial membrane potential (ΔΨm), accumulation of reactive oxygen species (ROS), decrease in Bcl-2, increase in BAX and Bad, translocation of Cytochrome <i>c</i>, activation of Caspase-9, -3, and cleavage of PARP. These results indicated that compound <b>1</b> would be a promising candidate against HCC through G0/G1 cell cycle arrest-related proliferation inhibition and mitochondrial pathway-dependent apoptosis.