Involvement of NO/cGMP signaling in the apoptotic and anti-angiogenic effects of β-lapachone on endothelial cells in vitro
Journal
Journal of Cellular Physiology
Journal Volume
211
Journal Issue
2
Pages
522-532
Date Issued
2007
Author(s)
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. ? 2006 Wiley-Liss, Inc.
SDGs
Other Subjects
beta lapachone; calcium; calcium chelating agent; calpain; calpastatin; caspase; cyclic GMP; nitric oxide; antiangiogenic activity; antineoplastic activity; antiviral activity; apoptosis; article; calcium cell level; cell growth; cell migration; cell protection; controlled study; endothelium cell; enzyme activation; enzyme regulation; human; human cell; in vitro study; membrane potential; mitochondrial membrane; neovascularization (pathology); nonhuman; priority journal; signal transduction; Tabebuia; tumor vascularization; vascular endothelium; Angiogenesis Inhibitors; Apoptosis; Arginine; Calcium; Calpain; Caspases; Cell Line; Cell Survival; Chelating Agents; Cyclic GMP; Dose-Response Relationship, Drug; Egtazic Acid; Endothelial Cells; Enzyme Activation; Enzyme Inhibitors; Humans; Leupeptins; Membrane Potential, Mitochondrial; Naphthoquinones; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Oligopeptides; Signal Transduction; Time Factors; Tabebuia avellanedae
Type
journal article