A Novel Ca2+/Calmodulin Antagonist HBC Inhibits Angiogenesis and Down-regulates Hypoxia-inducible Factor

Jung, Hye Jin; Kim, Jong Hyeon; Shim, Joong Sup; Kwon, Ho Jeong

doi:10.1074/jbc.m110.135632

Cited by 32 publications

(19 citation statements)

References 49 publications

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“…While in pharmacologically or genetically HIF-1α-depleted mice, CNV was significantly suppressed with reduction of intraocular VEGF and/or ICAM-1 [23], [81]–[84]. Here, our results demonstrated that the HIF−1α activation induced by laser treatment was significantly suppressed by curcumin, which are compatible with previous results that curcumin or its derivate had the ability to down-regulated HIF−1α and VEGF expression in vascular endothelial cells and blocked angiogenesis in vitro [85]–[86]. Our data, at least in part, also suggest that the suppression of the expression of angiogenic and inflammatory molecules observed after laser injury is due to curcumin-induced inhibition of the NF-κB and HIF−1α pathway.…”

Section: Discussionsupporting

confidence: 91%

Suppression of Experimental Choroidal Neovascularization by Curcumin in Mice

et al. 2012

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PurposeTo investigate the effects of curcumin on the development of experimental choroidal neovascularization (CNV) with underlying cellular and molecular mechanisms.MethodsC57BL/6N mice were pretreated with intraperitoneal injections of curcumin daily for 3 days prior to laser-induced CNV, and the drug treatments were continued until the end of the study. The CNV area was analyzed by fluorescein-labeled dextran angiography of retinal pigment epithelium (RPE)-choroid flat mounts on day 7 and 14, and CNV leakage was evaluated by fluorescein angiography (FA) on day 14 after laser photocoagulation. The infiltration of F4/80 positive macrophages and GR-1 positive granulocytes were evaluated by immunohistochemistry on RPE-choroid flat mounts on day 3. Their expression in RPE-choroid complex was quantified by real-time PCR (F4/80) and Western blotting (GR-1) on day 3. RPE-choroid levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, and intercellular adhesion molecule (ICAM)-1 were examined by ELISA on day 3. Double immunostaining of F4/80 and VEGF was performed on cryo-sections of CNV lesions on day 3. The expression of nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)−1α in the RPE-choroid was determined by Western blotting.ResultsCurcumin-treated mice had significantly less CNV area (P<0.05) and CNV leakage (P<0.001) than vehicle-treated mice. Curcumin treatment led to significant inhibition of F4/80 positive macrophages (P<0.05) and GR-1 positive granulocytes infiltration (P<0.05). VEGF mainly expressed in F4/80 positive macrophages in laser injury sites, which was suppressed by curcumin treatment (P<0.01). Curcumin inhibited the RPE-choroid levels of TNF-α (P<0.05), MCP-1 (P<0.05) and ICAM-1 (P<0.05), and suppressed the activation of NF-κB in nuclear extracts (P<0.05) and the activation of HIF−1α (P<0.05).ConclusionCurcumin treatment led to the suppression of CNV development together with inflammatory and angiogenic processes including NF-κB and HIF−1α activation, the up-regulation of inflammatory and angiogenic cytokines, and infiltrating macrophages and granulocytes. This provides molecular and cellular evidence of the validity of curcumin supplementation as a therapeutic strategy for the suppression of age-related macular degeneration (AMD)-associated CNV.

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Section: Discussionsupporting

confidence: 91%

Suppression of Experimental Choroidal Neovascularization by Curcumin in Mice

et al. 2012

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“…Curcumin potently inhibited HIF1A protein production both in rodent endocrine pituitary tumour cell lines and in cells of different human pituitary adenoma types. This has also been observed for curcumin and its derivatives in a variety of cell lines serving as models of different types of tumours (Bae et al 2006, Thomas et al 2008, Jung et al 2010, Ströfer et al 2011.…”

Section: Discussionmentioning

confidence: 85%

Curcumin suppresses HIF1A synthesis and VEGFA release in pituitary adenomas

Shan

Schaaf

Schmidt³

et al. 2012

Journal of Endocrinology

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Curcumin (diferuloylmethane), a polyphenolic compound derived from the spice plantCurcuma longa, displays multiple actions on solid tumours including anti-angiogenic effects. Here we have studied in rodent and human pituitary tumour cells the influence of curcumin on the production of hypoxia inducible factor 1α (HIF1A) and vascular endothelial growth factor A (VEGFA), two key components involved in tumour neovascularisation through angiogenesis. Curcumin dose-dependently inhibited basal VEGFA secretion in corticotroph AtT20 mouse and lactosomatotroph GH3 rat pituitary tumour cells as well as in all human pituitary adenoma cell cultures (n=32) studied. Under hypoxia-mimicking conditions (CoCl2treatment) in AtT20 and GH3 cells as well as in all human pituitary adenoma cell cultures (n=8) studied, curcumin strongly suppressed the induction of mRNA synthesis and protein production of HIF1A, the regulated subunit of the hypoxia-induced transcription factor HIF1. Curcumin also blocked hypoxia-induced mRNA synthesis and secretion of VEGFA in GH3 cells and in all human pituitary adenoma cell cultures investigated (n=18). Thus, curcumin may inhibit pituitary adenoma progression not only through previously demonstrated anti-proliferative and pro-apoptotic actions but also by its suppressive effects on pituitary tumour neovascularisation.

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“…It is well documented that HIF-1α activation is required for cellular protection and metabolic alterations followed by oxygen deprivation in tumors, making it the main regulator of cancer cell survival (Powis and Kirkpatrick 2004). It is of utmost importance that an increasing number of studies highlight the implication of Ca 2+ signaling in the regulation of the HIF-1α subunit (Jung et al 2010;BerchnerPfannschmidt et al 2004;Seta et al 2004;Hui et al 2006;Liu et al 2007;Werno et al 2008;Yuan et al 2008;Lin et al 2009). Specifically, it has been o b s e r v e d t h a t t h e e f f e c t o f 1 , 2 -b i s ( oaminophenoxy)ethane-N,N,N,N,-tetraacetic acid tetra-(acetoxymethyl)-ester (BAPTA-AM) in human aortic smooth muscle and human umbilical vein endothelial cells leads to increased protein levels of HIF-1α (Oda et al 2009).…”

Section: Introductionmentioning

confidence: 98%

Differential effects of calcium on PI3K-Akt and HIF-1α survival pathways

et al. 2016

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Calcium signaling participates in the regulation of numberless cellular functions including cell cycle progression and cellular migration, important processes for cancer expansion. Cancer cell growth, migration, and invasion are typically supported by PI3K/Akt activation, while a hypoxic environment is critical in cancer development. Accordingly, in the present study, we aimed at investigating whether perturbations in calcium homeostasis induce alterations of HIF-1α and activate Akt levels in epithelial A549 and A431 cells. Survival was drastically reduced in the presence of calcium chelator BAPTA-AM and thapsigargin, a SERCA inhibitor inducing store-operated calcium entry, to a lesser extent. Calcium chelation provoked a transient but strong upregulation of HIF-1α protein levels and accumulation in the nucleus, whereas in the presence of thapsigargin, HIF-1α levels were rapidly abolished before reaching and exceeding control levels. Despite cell death, calcium chelation merely inhibited Akt, which was significantly activated in the presence of thapsigargin. Moreover, when store-operated calcium entry was simulated by reintroducing calcium ions in cell suspensions, Akt was rapidly activated in the absence of any growth factor. These data further underscore the growing importance of calcium entry and directly link this elementary event of calcium homeostasis to the Akt pathway, which is commonly deregulated in cancer.

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A Novel Ca2+/Calmodulin Antagonist HBC Inhibits Angiogenesis and Down-regulates Hypoxia-inducible Factor

Cited by 32 publications

References 49 publications

Suppression of Experimental Choroidal Neovascularization by Curcumin in Mice

Suppression of Experimental Choroidal Neovascularization by Curcumin in Mice

Curcumin suppresses HIF1A synthesis and VEGFA release in pituitary adenomas

Differential effects of calcium on PI3K-Akt and HIF-1α survival pathways

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