Tanshinone IIA isolated from Salvia miltiorrhiza elicits the cell death of human endothelial cells.
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.
Yang
Li-Jyun
LJ
Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, 155 Li-Nung Street, Sec. 2, Shih-pai,Taipei, 112, Taiwan.
Jeng
Chung-Jiuan
CJ
Kung
Hsiu-Ni
HN
Chang
Cheng-Chi
CC
Wang
An-Guor
AG
Chau
Gar-Yang
GY
Don
Ming-Jaw
MJ
Chau
Yat-Pang
YP
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
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