Involvement of NO/cGMP signaling in the apoptotic and anti-angiogenic effects of β-lapachone on endothelial cells in vitro
✍ Scribed by Hsiu-Ni Kung; Chung-Liang Chien; Gar-Yang Chau; Ming-Jaw Don; Kuo-Shyan Lu; Yat-Pang Chau
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 588 KB
- Volume
- 211
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Neovascularization is an essential process in tumor development, it is conceivable that anti‐angiogenic treatment may block tumor growth. In angiogenesis, nitric oxide (NO) is an important factor which mediates vascular endothelial cell growth and migration. β‐Lapachone (3,4‐dihydro‐2,2‐dimethyl‐2H‐naphtho‐[1,2‐b]pyran‐5,6‐dione), a natural product extracted from the lapacho tree (Tabebuia avellanedae), has been demonstrated to possess anti‐cancer and anti‐viral effects. Whether β‐lapachone can induce endothelial cell death or has an anti‐angiogenic effect is still an enigma. We investigated the in vitro effect of β‐lapachone on endothelial cells, including human vascular endothelial cell line, EAhy926, and human umbilical vascular endothelial cells (HUVEC). Our results revealed that (1) the intracellular cGMP levels and the mitochondria membrane potential (MMP) decreased, and calpain and caspases were activated, during β‐lapachone‐induced endothelial cell death; (2) co‐treatment with calpain inhibitors (ALLM or ALLN) or the intracellular calcium chelator, BAPTA, but not the general caspase inhibitor, zVAD‐fmk, provided significant protection against apoptosis by preventing the β‐lapachone‐induced MMP decrease and cytoplasmic calcium increase; (3) addition of NO downregulated the β‐lapachone‐induced cGMP depletion and protected the cells from apoptosis by blocking the MMP decrease and the calcium increase; and (4) exogenous NO protects endothelial cells against the cell death induced by β‐lapachone, but not the anti‐angiogenic effect. From all the data above, we demonstrated that NO can attenuate the apoptotic effect of β‐lapachone on human endothelial cells and suggest that β‐lapachone may have potential as an anti‐angiogenic drug. J. Cell. Physiol. 211: 522–532, 2007. © 2006 Wiley‐Liss, Inc.