Ginkgol C17：1 has been shown to inhibit apoptosis and migration of cancer cells,but the underlying mechanisms are not fully elucidated.In this study,we explored whether the inhibitory effects of Ginkgol C17：1 were a...Ginkgol C17：1 has been shown to inhibit apoptosis and migration of cancer cells,but the underlying mechanisms are not fully elucidated.In this study,we explored whether the inhibitory effects of Ginkgol C17：1 were associated with epidermal growth factor receptor（EGFR） and PI3K/Akt signaling.The results showed that EGF treatment increased the phosphorylation of EGFR,PI3 K,Akt,mTOR and NF-κB,and also enhanced the proliferation,migration and invasion of HepG2 cells.Ginkgol C17：1 dose-dependently inhibited EGF-induced phosphorylation/activation of all the key components including EGFR,PI3 K,Akt,mTOR and NF-kB,leading to a significant reduction either of proliferation or migration and invasion of HepG2 cells.Notably,treatment with Ginkgol C17：1 in mice suppressed the growth of tumor mass in vivo,and expression of EGFR in the tumor tissue.The results suggest that Ginkgol C17：1 is a potent tumor inhibiting compound that acts on EGF-induced signal transduction of the PI3K/Akt signaling pathways,and may represent a clinically interesting candidate for cancer therapy.展开更多
Pharmacological activities and adverse side effects of ginkgolic acids(GAs), major components in extracts from the leaves and seed coats of Ginkgo biloba L, have been intensively studied. However, there are few report...Pharmacological activities and adverse side effects of ginkgolic acids(GAs), major components in extracts from the leaves and seed coats of Ginkgo biloba L, have been intensively studied. However, there are few reports on their hepatotoxicity. In the present study, the metabolism and hepatotoxicity of GA(17:1), one of the most abundant components of GAs, were investigated. Kinetic analysis indicated that human and rat liver microsomes shared similar metabolic characteristics of GA(17:1) in phase I and II metabolisms. The drug-metabolizing enzymes involved in GA(17:1) metabolism were human CYP1 A2, CYP3 A4, UGT1 A6, UGT1 A9, and UGT2 B15, which were confirmed with an inhibition study of human liver microsomes and recombinant enzymes. The MTT assays indicated that the cytotoxicity of GA(17:1) in HepG2 cells occurred in a time-and dose-dependent manner. Further investigation showed that GA(17:1) had less cytotoxicity in primary rat hepatocytes than in HepG2 cells and that the toxicity was enhanced through CYP1 A-and CYP3 A-mediated metabolism.展开更多
基金supported by the National Natural Science Foundation of China(grant no.81372404)the Postdoctoral Foundation of China(grant no.2012M521018)to Yueying Lithe Zhenjiang Social Development Project(No.SH2015072)to Yaxiang Shi
文摘Ginkgol C17：1 has been shown to inhibit apoptosis and migration of cancer cells,but the underlying mechanisms are not fully elucidated.In this study,we explored whether the inhibitory effects of Ginkgol C17：1 were associated with epidermal growth factor receptor（EGFR） and PI3K/Akt signaling.The results showed that EGF treatment increased the phosphorylation of EGFR,PI3 K,Akt,mTOR and NF-κB,and also enhanced the proliferation,migration and invasion of HepG2 cells.Ginkgol C17：1 dose-dependently inhibited EGF-induced phosphorylation/activation of all the key components including EGFR,PI3 K,Akt,mTOR and NF-kB,leading to a significant reduction either of proliferation or migration and invasion of HepG2 cells.Notably,treatment with Ginkgol C17：1 in mice suppressed the growth of tumor mass in vivo,and expression of EGFR in the tumor tissue.The results suggest that Ginkgol C17：1 is a potent tumor inhibiting compound that acts on EGF-induced signal transduction of the PI3K/Akt signaling pathways,and may represent a clinically interesting candidate for cancer therapy.
基金supported by the National Key Project of China(No.2017YFC0908600)the National Natural Science Foundation of China(No.81173120)the National Natural Science Foundation of Zhejiang Province(No.LQ15H310003)
文摘Pharmacological activities and adverse side effects of ginkgolic acids(GAs), major components in extracts from the leaves and seed coats of Ginkgo biloba L, have been intensively studied. However, there are few reports on their hepatotoxicity. In the present study, the metabolism and hepatotoxicity of GA(17:1), one of the most abundant components of GAs, were investigated. Kinetic analysis indicated that human and rat liver microsomes shared similar metabolic characteristics of GA(17:1) in phase I and II metabolisms. The drug-metabolizing enzymes involved in GA(17:1) metabolism were human CYP1 A2, CYP3 A4, UGT1 A6, UGT1 A9, and UGT2 B15, which were confirmed with an inhibition study of human liver microsomes and recombinant enzymes. The MTT assays indicated that the cytotoxicity of GA(17:1) in HepG2 cells occurred in a time-and dose-dependent manner. Further investigation showed that GA(17:1) had less cytotoxicity in primary rat hepatocytes than in HepG2 cells and that the toxicity was enhanced through CYP1 A-and CYP3 A-mediated metabolism.
