α-pinene regulates miR-221 and induces G(2)/M phase cell cycle arrest in human hepatocellular carcinoma cells

The naturally occurring compound α-pinene induces cell cycle arrest and antitumor activity. We examined effects of α-pinene on cell cycle regulation in hepatocellular carcinoma cells (HepG2) cells to establish a foundation for its development as a novel treatment for hepatocellular carcinoma (HCC). HepG2 cells treated with α-pinene exhibited dose-dependent growth inhibition as a result of G(2)/M-phase cell cycle arrest. Cell cycle arrest was associated with down-regulated cyclin-dependent kinase 1 (CDK1) and miR-221 levels and up-regulated levels of CDKN1B/p27, γ-H2AX, phosphorylated ATM, phosphorylated Chk2 and phosphorylated p53. Our observations are consistent with a model in which α-pinene inhibits miR221 expression, which leads to G(2)/M-phase arrest and activation of CDKN1B/p27-CDK1 and ATM-p53-Chk2 pathways that suppress human hepatoma tumor progression. Additionally, α-pinene was found to trigger oxidative stress and induce apoptosis of HepG2 cells. α-pinene, therefore, represents a potential chemotherapeutic compound for the treatment of HCC.