Involvement of NO/cGMP signaling in the apoptotic and anti‐angiogenic effects of β‐lapachone on endothelial cells in vitro

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. beta-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 beta-lapachone can induce endothelial cell death or has an anti-angiogenic effect is still an enigma. We investigated the in vitro effect of beta-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 beta-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 beta-lapachone-induced MMP decrease and cytoplasmic calcium increase; (3) addition of NO downregulated the beta-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 beta-lapachone, but not the anti-angiogenic effect. From all the data above, we demonstrated that NO can attenuate the apoptotic effect of beta-lapachone on human endothelial cells and suggest that beta-lapachone may have potential as an anti-angiogenic drug.

In vitro and in vivo anti-inflammatory effects of taheebo, a water extract from the inner bark of Tabebuia avellanedae

“…Recently, various fractions have been obtained from Tabebuia avellanedae and were reported to display astringent, anti-inflammatory, anti-bacterial, anti-fungal, diuretic, anti-coagulational, and laxative properties as well as an anti-cancer effect (Choi et al, 2003;Machado et al, 2003;Awale et al, 2005;Bohler et al, 2008). The major active compounds identified in the hot water extract include naphthoquinones, furanonaphthoquinones, anthraquinones, benzoic acid derivatives, benzaldehyde derivatives, iridoids, coumarins, and flavonoids (Kreher et al, 1988;Ueda et al, 1994;Choi et al, 2003;Machado et al, 2003;Pereira et al, 2006;Kim et al, 2007;Kung et al, 2007). Despite its wide-range of pharmacological actions, relatively few studies have investigated the anti-inflammatory activity of Tabebuia avellanedae inner bark compounds and their effect and mechanism in treating inflammatory diseases.…”

β-lapachone-Induced Apoptosis of Human Gastric Carcinoma AGS Cells Is Caspase-Dependent and Regulated by the PI3K/Akt Pathway

“…However, pretreatment with the pan-caspase inhibitor, z-VAD-fmk, significantly attenuated the cleavage of caspase-3 and PARP induced by β-lapachone, and reduced β-lapachone-induced cell death and growth inhibition (Fig. 4), confirming that β-lapachone-induced apoptosis is caspase-dependent which was similar to other reports (Shiah et al ., 1999; Gupta et al ., 2002; Woo et al ., 2006; Kung et al ., 2007; Moon et al ., 2010). …”

N-benzyl-5-phenyl-1H-pyrazole-3-carboxamide promotes vascular endothelial cell angiogenesis and migration in the absence of serum and FGF-2

“…NO, a highly diffusible intercellular signaling molecule with a wide range of biological effects, is generated by nitric oxide synthase (NOS), which catalyzes the conversion of L-arginine to L-citrulline [27] . Since it was discovered 20 years ago, NO has been found to play an important role in angiogenesis and in the nervous and immune systems.…”