title: Tanshinone IIA isolated from Salvia miltiorrhiza elicits the cell death of human endothelial cells.
abstract: Tanshinone IIA, a major component extracted from the traditional herbal medicine, Salvia miltiorrhiza Bunge, is known to exhibit potent cytotoxicity against various human carcinoma cells in vitro. However, the mechanism by which tanshinone IIA produces this anti-tumor effect remains unknown. Since anti-neovascularization has generally been regarded as an effective strategy for anti-cancer therapy, we decided to investigate the mechanism underlying tanshinone IIA-mediated death of human endothelial cells. In this study, we demonstrate that tanshinone IIA elicits human endothelial cell death independent of oxidative stress. These events are partially calcium-dependent and actually dependent upon NAD(P)H: quinone oxidoreductase (NQO1) activity. Tanshinone IIA induces an increase in intracellular calcium, which triggers the release of cytochrome c, thus causing loss of the mitochondrial membrane potential (MMP), resulting in the subsequent activation of caspases. Blocking the induction of Ca2+ perturbation with BAPTA-AM partially rescued cells from tanshinone IIA-induced cytotoxicity. Additionally, blocking NQO1 activity with dicoumoral or inhibiting caspase activities with the general caspase inhibitor, z-VAD-fmk, prevented cell death induced by tanshinone IIA. Therefore, our results imply that tanshinone IIA-mediated cytotoxicity against human endothelial cells may occur through activation of NQO1, which induces a calcium imbalance and mitochondrial dysfunction, thus stimulating caspase activity.
authors.affiliation: Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, 155 Li-Nung Street, Sec. 2, Shih-pai,Taipei, 112, Taiwan.
authors.forename: Li-Jyun
authors.initials: LJ
authors.lastname: Yang
authors.forename: Chung-Jiuan
authors.initials: CJ
authors.lastname: Jeng
authors.forename: Hsiu-Ni
authors.initials: HN
authors.lastname: Kung
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: An-Guor
authors.initials: AG
authors.lastname: Wang
authors.forename: Gar-Yang
authors.initials: GY
authors.lastname: Chau
authors.forename: Ming-Jaw
authors.initials: MJ
authors.lastname: Don
authors.forename: Yat-Pang
authors.initials: YP
authors.lastname: Chau
mesh_terms: D045784:Abietanes; D000165:Acridine Orange / Q000494:pharmacology; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D016923:Cell Death; D045304:Cytochromes c / Q000378:metabolism; D001728:Dicumarol / Q000494:pharmacology; D004365:Drugs, Chinese Herbal; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D018384:Oxidative Stress; D010616:Phenanthrenes / Q000494:pharmacology*; D010936:Plant Extracts; D017382:Reactive Oxygen Species / Q000378:metabolism; D027561:Salvia miltiorrhiza / Q000378:metabolism*; D013997:Time Factors
chemical_list: D045784:Abietanes; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D010616:Phenanthrenes; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C021751:tanshinone; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D001728:Dicumarol; D045304:Cytochromes c; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D020169:Caspases; D000165:Acridine Orange; D002118:Calcium