Tanshinone IIA isolated from Salvia miltiorrhiza elicits the cell death of human endothelial cells |
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Authors: | Li-Jyun?Yang Chung-Jiuan?Jeng Hsiu-Ni?Kung Cheng-Chi?Chang An-Guor?Wang Gar-Yang?Chau Ming-Jaw?Don Email author" target="_blank">Yat-Pang?ChauEmail author |
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Institution: | (1) Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, 155 Li-Nung Street, Sec. 2,, Shih-pai,Taipei, 112, Taiwan;(2) Department of Medicine, College of Medicine, Fu-Jen Catholic University, Taiwan;(3) Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, Taiwan;(4) Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan;(5) Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital-Taipai, 201 Shih-Pai Road, Sec. 2, Taipei, 217, Taiwan;(6) National Research Institute of Chinese Medicine, 155-1, Li-Nang Street, Sec. 2, Shih-Pai, Taipei, 112, Taiwan |
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Abstract: | Summary 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.These authors contributed equally to this work. |
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Keywords: | human endothelial cells NQO1 activity tanshinone IIA |
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