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

Abstract

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.

Phytochemicals in Cancer Treatment: From Preclinical Studies to Clinical Practice

“…They possess complementary and overlapping mechanisms to slow down the carcinogenic process by scavenging free radicals (Lee et al, 2013), suppressing survival and proliferation of malignant cells (Yan et al, 2018), as well as diminishing invasiveness and angiogenesis of tumors (Lu et al, 2018a). They exert wide and complex range of actions on different molecular targets and signal transduction pathways including membrane receptors (Deng et al, 2017), kinases (Dou et al, 2018), downstream tumor-activator or -suppressor proteins (Adams et al, 2010), transcriptional factors (Zhang et al, 2017b), microRNAs (miRNAs) (Cojocneanu et al, 2015), cyclins, and caspases (Yan et al, 2018).…”

“…Dicumarol (DIC) is the natural anticoagulant derived from coumarin, by bacterial action in spoiled sweet clover hay (Melilotus officinalis, Fabaceae). In BALB/c nude mouse xenograft model, DIC (30 mg/kg) significantly suppressed the growth of SKOV3 ovarian carcinoma cells (Zhang et al, 2017b). The in vitro molecular mechanistic studies suggested that DIC STAT3 and associated protein (Zhu et al, 2016;Odeh et al, 2018) Ursolic acid (triterpenoids) Oldenlandia diffusa (Rubiaceae)…”

Chemoresistance in ovarian cancer: exploiting cancer stem cell metabolism

“…PDK1 is also highly expressed in chemoresistant ovarian cancer cells [ 63 ]. Dicumarol could inhibit PDK1 activity, shifting the glucose metabolism from aerobic glycolysis to OXPHOS, increasing ROS levels, and inducing apoptosis in vitro and in vivo in ovarian cancer [ 64 ].…”

PDK1 promotes ovarian cancer metastasis by modulating tumor-mesothelial adhesion, invasion, and angiogenesis via α5β1 integrin and JNK/IL-8 signaling

“…PDK1 was overexpressed in the highly glycolytic human ovarian cancer cell line OC316 compared with the less glycolytic cell line IGROV-1 21 . Dicumarol, a coumarin compound, has been found to inhibit PDK1 and suppress ovarian cancer tumor growth in vivo 22 . A recent study demonstrated PDK1 contributes to cisplatin resistance of ovarian cancer through EGFR activation and promotes epithelial-mesenchymal transition 23 .…”