title: GdCl3 induced Hep G2 cell death through mitochondrial and external death pathways without significant elevation of ROS generation.
abstract: Gadolinium (Gd) compounds have important applications as MRI contrast and potential anticancer agents. The present study investigated the mechanisms of the proapoptotic effect of gadolinium chloride (GdCl(3)) on hepatoblastoma cell line (Hep G2) tumor cells. The experimental results indicated that GdCl(3) induced apoptosis of Hep G2 at high concentration and with long time incubation; however, unlike the actions on normal cell lines, GdCl(3) did not cause any oxidative stress on tumor cells. Cytochrome c (Cyt c) and apoptosis inducing factor release, Bax translocation, collapse of mitochondria membrane potential, caspase 3 and 8 activation, and Bid cleavage were observed along with a sustained activation of extracellular signal-regulated kinase (ERK) and c-Jun NH2 terminal kinase (JNK). Addition of ERK and JNK inhibitor attenuated the effect of GdCl(3) induced apoptosis and Cyt c release. All the results suggested a novel mechanism that GdCl(3) induced Hep G2 cell death through intrinsic and external death pathways without significant elevation of reactive oxygen species generation. The present work provided new insight to understand the mechanisms of the biological effects of GdCl(3) and implications for the development of anticancer Gd agents.
authors.affiliation: State Key Laboratories of Natural and Biomimetic Drugs, Peking University, Beijing, People's Republic of China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ye
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shi
authors.forename: Huixue
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaoda
authors.initials: X
authors.lastname: Yang
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D005682:Gadolinium / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D005682:Gadolinium; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8; C038958:gadolinium chloride