Ginkgo biloba induces different gene expression signatures of oncogenic pathways in malignant and non-malignant cells of the liver. Homo sapiens

Ginkgo biloba (EGb761) is a widely used botanical drug with diverse biological properties. Several reports indicate that EGb761 confers both preventive effects as well as anti-tumorigenic properties in a variety of tumors, including hepatocellular carcinoma (HCC). We here evaluate a differential functional and mechanistic effect of EGb761 on HCC cells and non-malignant hepatocytes. A reduced production of reactive oxygen species (ROS) in a state of oxidative stress was predominantly present in non-transformed IH. Further, EGb761 administration significantly impaired proliferation and induced apoptosis in all cell lines, but median IC50 for hepatoma cells was significantly lower than in IH confirming a differential response of EGb761 on normal and malignant cells. Consistently, EGb761 induced a significant reduction in both colony and sphere forming ability in hepatoma cells whereas treatment caused no mentionable changes in IH. Transcriptomic changes in hepatoma cells involved key oncogenic properties resembling proliferation and pro-survival signaling as well as xenobiotic and oxidative stress response. Comparative analyses of differentially affected molecular pathways centered on MAPK/ERK and PI3K/AKT/mTOR signaling. EGb761 has a differential effect in non-transformed and cancer cells. While treatment confers protective effects in non-malignant cells, treatment significantly impaired tumorigenic properties by affecting multiple molecular pathways. Results, therefore, indicate that EGb761 could be safely used for both preventive as well as therapeutic strategies in the liver. Overall design: Human hepatoma cell lines (Huh7, WRL68), primary human HCC cells (PItts1) and immortalized human hepatocytes (THLE5B) were exposed to various concentrations (0 - 1000 μg/ml) of EGb761. Effects on apoptosis and proliferation were evaluated after 72h of EGb761 exposure and IC50 concentration was defined for each cell line and used for further experiments. Response to oxidative stress and tumorigenic properties of the cells such as sphere and colony formation were investigated. Molecular changes were assessed by gene expression microrarrays and western blotting. Effects of EGb761 treatment was compared to non-treated controls.