Dr. hepatocytes (IH) were exposed to various concentrations (0C1000 g/ml) of EGb761. Apoptosis and proliferation MCC-Modified Daunorubicinol were evaluated after 72h of EGb761 exposure. Response to oxidative stress, tumorigenic properties and molecular changes were further investigated. While anti-oxidant effects were detected in all cell lines, EGb761 promoted anti-proliferative and pro-apoptotic effects MCC-Modified Daunorubicinol mainly in hepatoma cells. Consistently, EGb761 treatment caused a significant reduction in colony and sphere forming ability in hepatoma cells and no mentionable changes in IH. Transcriptomic changes involved oxidative stress response as well as key oncogenic pathways resembling Nrf2- and mTOR signaling pathway. Taken together, EGb761 induces differential effects in non-transformed and cancer cells. While treatment confers protective effects in MCC-Modified Daunorubicinol non-malignant cells, EGb761 significantly impairs tumorigenic properties in cancer cells by affecting key oncogenic pathways. Results provide the rational for clinical testing of EGb761 in preventive and therapeutic strategies in human liver diseases. Introduction Hepatocellular carcinoma is the third leading cause of cancer-related death in men and the fifth in women and shows an increasing incidence in the Western world.[1] The majority of HCCs develop in the background of a chronic inflammatory liver damage subsequently leading to liver cirrhosis.[2] In this context, several predisposing risk factors, such as chronic viral hepatitis, alcohol abuse and metabolic disorders have been identified to promote HCC development, e.g. by increased production of oxidative stress.[3] The constant tissue remodeling and inflammation further enhance intra- and inter-tumor heterogeneity characteristic for HCCs.[4] In line with this, it has also been shown, that the combination of driving oncogenes and type of underlying changes in the hepatic microenvironment define the tumor phenotype highlighting the importance of preventive approaches in clinical management of liver diseases.[5] Recently, it has been reported that anti-oxidant properties of Ginkgo biloba induce hepatoprotective effects in non-malignant liver injuries [6C9] as well as preventive effects against liver tumor initiation.[10] Ginkgo biloba extract is an herbal supplement obtained from the leaves of the ginkgo tree. Ginkgo has been extensively administrated over centuries in traditional Chinese medicine.[11] Due to its anti-oxidant and cytoprotective properties it is currently one of the most widely used botanical compounds worldwide. It is administrated for the prevention and treatment of a variety of diseases such as cognitive function disorders, peripheral blood flow insufficiency, tinnitus and vertigo.[12C15] EGb761 is a well-defined standard Ginkgo biloba extract made up of 22C24% flavone glycosides (primarily quercetin, kaempferol and isorhamnetin) and 6% terpene lactones (2,8C3,4% ginkgolides A, B and C and 2,6C3,2% bilobalide).[16] The active constituents of EGb761 seem to exert its effects through interaction with multiple molecular mechanisms and signaling pathways. An ERK1/2-signaling and cell cycle control gene-dependent regulation has been proposed in gastric cancer[17, 18], steroidogenesis pathways and aromatase activity in breast malignancy cells [19, 20], the mitochondrial pathway of apoptosis in melanoma[21] or STAT3-activity in prostate cancer cells [22] has been described. However, the exact molecular mechanisms underlying protective and anti-tumorigenic effects of EGb761 in the liver are not yet fully comprehended. Here, we assessed transcriptomic changes of hepatoma Rabbit Polyclonal to OR10C1 cells as well as immortalized hepatocytes (IH) induced by a short-term treatment with EGb761. We confirm that EGb761 possess anti-oxidant as well as anti-tumor properties and show that it acts through a specific deregulation of.