Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells.


Zhang, Wenjia; Su, Jing; Xu, Huadan; Yu, Shanshan; Liu, Yanan; Zhang, Yong; Sun, Liankun; Yue, Ying; Zhou, Xiaoli

Publication Year 1905
Journal Plos One
Pages e0179672
Volume 12
Issue 6
PMID 28617852.0
PMCID PMC5472302
DOI 10.1371/journal.pone.0179672
URL http://dx.doi.org/10.1371/journal.pone.0179672

Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in ovarian cancer and thus is a promising anticancer therapeutic target. Our previous work suggests that coumarin compounds are potential inhibitors of PDKs. In this study, we used the ovarian cancer cell line SKOV3 as the model system and examined whether dicumarol (DIC), a coumarin compound, could inhibit ovarian cancer through targeting PDK1. We showed that DIC potently inhibited the kinase activity of PDK1, shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of reactive oxygen species (ROS), attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability in vitro. The same phenotypes induced by DIC also were translated in vivo, leading to significant suppression of xenograft growth. This study not only identifies a novel inhibitor for PDK1, but it also reveals novel anticancer mechanisms of DIC and provides a promising anticancer therapy that targets the Warburg effect.