NS398 reduces hypoxia‐inducible factor (HIF)‐1α and HIF‐1 activity: Multiple‐level effects involving cyclooxygenase‐2 dependent and independent mechanisms

Zhong, Hua; Willard, Margaret T.; Simons, Jonathan W.

doi:10.1002/ijc.20438

Cited by 52 publications

(45 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The role of hypoxia in the regulation of COX-2, on the other hand, was found to be an up-regulation of Cox-2 protein levels and correlated with hypoxia-inducible factor (HIF)-1α induction. A feedback loop, similar to SAG turnover, was reported in COX-2 pathway, in which COX-2/PGE2 up-regulation due to hypoxia enhances HIF-1α transcriptional activity and this reinforces COX-2 up-regulation through a feedback mechanism [52,53]. BNIP3 was another protein we tested in our panel.…”

Section: Discussionsupporting

confidence: 52%

Apoptotic Effects of Etodolac in Breast Cancer Cell Cultures

Orun¹,

Tiber²,

Sevinç³

2017

Nonsteroidal Anti-Inflammatory Drugs

View full text Add to dashboard Cite

Nonsteroidal anti-inlammatory drugs (NSAIDs) are commonly used as anti-inlammatory and analgesic agents. This family of drugs suppresses prostaglandin synthesis through inhibition of cyclooxygenase (COX) enzymes. Recent studies displayed that anti-carcinogenic actions of these drugs are mediated by COX-2 enzyme. Currently, there is intense research on COX-2 inhibitors as therapeutic targets. Etodolac is not perfectly selective but shows 'preferential selectivity' for COX-2. Here, in this study, we wanted to take gene expression snapshots of several apoptotic proteins under diferent conditions of drug exposure. The aim, therefore, focused to determine diferential efects of etodolac on the regulation of apoptotic genes in hormone-responsive MCF-7 and triple-negative MDA-MB-231 cancer cell lines. Our data suggest that MDA-MB-231 is more responsive to etodolac exposure. Cell proliferation and apoptosis consistently regulated upon drug addiction. Furthermore, COX-2/HER2 was explicitly an up-regulated, phosphorylated form of Bad accumulated and anti-apoptotic proteins SAG and survivin increased in both transcriptional and translational levels. Changes in mitochondrial Bcl-2 family proteins were moderate and pro-and anti-apoptotic proteins showed similar levels of regulation in both cell lines. We believe that these indings would be supportive for future studies targeting etodolac-based therapies, as it reveals apoptotic factors diferentially regulated in hormone-responsive and invasive cell lines.Keywords: apoptosis, MCF-7, MDA-MB-231, MTT, Bad, SAG © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. IntroductionNonsteroidal anti-inlammatory drugs (NSAIDs), regularly used for their anti-inlammatory and analgesic efects, were shown to have potency for cancer prevention as well [1,2]. This family of drugs suppresses prostaglandin synthesis through inhibition of cyclooxygenase (COX) enzymes. COX enzymes have two isoforms COX-1 and COX-2, with a recent addition of a splice variant of COX-1, COX-3, which is not functional in humans. COX-1 is commonly expressed in body, showing constitutive activation. COX-2, on the other hand, is hardly detectable in normal conditions but is induced upon stimulation by mitogenic agents, cytokines, growth factors, and so on. Later reports, however, demonstrated that COX-2 is also constitutively expressed in basal levels at several tissues including gastric mucosa, developing brain or kidney [3][4][5].COX isoforms catalyse prostaglandin G/H (PGG2/PGH2) synthesis from arachidonic acid, and these prostaglandins are then converted to stable forms like PGD2, PGE2, PGF2, prostacyclin (PGI2) or thromboxane A2 (TXA2) depending on the cell type. Inhibition of COX enzymes, therefore, could result in improper prostaglandin activity, which in turn may ca...

show abstract

Section: Discussionsupporting

confidence: 52%

Apoptotic Effects of Etodolac in Breast Cancer Cell Cultures

Orun¹,

Tiber²,

Sevinç³

2017

Nonsteroidal Anti-Inflammatory Drugs

View full text Add to dashboard Cite

show abstract

“…Furthermore, histopathologic changes in liver caused by LPS exposure are worsened by coexposure to an otherwise noninjurious reduction in inspired O 2 (Shibayama, 1987), suggesting that hypoxia increases either the degree of LPS-induced inflammation or the sensitivity of hepatocytes to the cytotoxic effects of inflammatory mediators. Interplay between hypoxia and inflammatory factors such as macrophages, cyclooxygenase-2, and PMNs has been reported (Hannah et al, 1995;Tamura et al, 2002;Lahat et al, 2003;Zhong et al, 2004).…”

Section: Hypoxia and Neutrophils In Lps/ran Liver Injury 1029mentioning

confidence: 99%

Coagulation-Mediated Hypoxia and Neutrophil-Dependent Hepatic Injury in Rats Given Lipopolysaccharide and Ranitidine

Luyendyk¹,

Shaw²,

Green³

et al. 2005

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Idiosyncrasy-like liver injury occurs in rats cotreated with nonhepatotoxic doses of ranitidine (RAN) and bacterial lipopolysaccharide (LPS). Hepatocellular oncotic necrosis is accompanied by neutrophil (PMN) accumulation and fibrin deposition in LPS/RAN-treated rats, but the contribution of PMNs to injury has not been shown. We tested the hypothesis that PMNs are critical mediators of LPS/RAN-induced liver injury and explored the potential for interaction between PMNs and hemostasisinduced hypoxia. Rats were given either LPS (44.4 ϫ 10 6 endotoxin units/kg) or its vehicle and then RAN (30 mg/kg) or its vehicle 2 h later. They were killed 3 or 6 h after RAN treatment, and hepatocellular injury was estimated from serum alanine aminotransferase activity and liver histopathology. Plasma PMN chemokine concentration and the number of PMNs in liver increased after LPS treatment at 3 h and were not markedly altered by RAN cotreatment. Depletion of circulating PMNs attenuated hepatic PMN accumulation and liver injury and had no effect on coagulation system activation. Anticoagulation with heparin attenuated liver fibrin deposition and injury in LPS/RAN-treated rats; however, heparin had little effect on liver PMN accumulation or plasma chemokine concentration. Liver hypoxia occurred in LPS/RAN-cotreated rats and was significantly reduced by heparin. In vitro, hypoxia enhanced the killing of rat hepatocytes by PMN elastase and shortened its onset, indicating a synergistic interaction between PMNs and hypoxia. The results suggest that PMNs are involved in the hepatocellular injury caused by LPS/RAN-cotreatment and that hemostasis increases sensitivity to PMN-induced hepatocellular injury by causing liver hypoxia.Ranitidine (RAN) is a histamine 2 receptor antagonist that is available over the counter and by prescription for treatment of several gastric hypersecretory conditions. RAN is associated with idiosyncratic hepatotoxicity in a small fraction (estimated at Ͻ0

show abstract

“…Hypoxia, inflammation, and angiogenesis, which are major processes of the tumor microenvironment, promote malignancy through an array of intertwined signals. Among these, hypoxia inducible factor-1α (HIF-1α) is a key player as it activates the transcription of multiple genes involved in tumor progression, which include vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2), hallmarks of angiogenesis and inflammation, respectively (1)(2)(3)(4).…”

mentioning

confidence: 99%

Inhibition of Hypoxia Inducible Factor-1α by Dihydroxyphenylethanol, a Product from Olive Oil, Blocks Microsomal Prostaglandin-E Synthase-1/Vascular Endothelial Growth Factor Expression and Reduces Tumor Angiogenesis

Terzuoli

Donnini²,

Giachetti³

et al. 2010

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: 2-(3,4-dihydroxyphenil)-ethanol (DPE), a polyphenol present in olive oil, has been found to attenuate the growth of colon cancer cells, an effect presumably related to its anti-inflammatory activity.Experimental Design: To further explore the effects of DPE on angiogenesis and tumor growth we investigated the in vivo efficacy of DPE in a HT-29 xenograft model and in vitro activities in colon cancer cells exposed to interleukin-1β (IL-1β) and prostaglandin E-2 (PGE-2).Results: DPE (10 mg/kg/day for 14 days) inhibited tumor growth, reducing vessel lumina and blood perfusion to tumor, and diminished expression of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and microsomal prostaglandin-E synthase-1 (mPGEs-1). In vitro, DPE (100 μmol/L) neither affected cell proliferation nor induced apoptosis in HT-29 and WiDr cells. DPE prevented the IL-1β-mediated increase of mPGEs-1 expression and PGE-2 generation, as it did the silencing of HIF-1α. Moreover, DPE blocked mPGEs-1-dependent expression of VEGF and inhibited endothelial sprouting induced by tumor cells in a coculture system. PGE-2 triggers a feed-forward loop involving HIF-1α, which impinges on mPGEs-1 and VEGF expression, events prevented by DPE via extracellular signal-related kinase 1/2. The reduction of PGE-2 and VEGF levels, caused by DPE, was invariably associated with a marked decrease in HIF-1α expression and activity, independent of proteasome activity, indicating that the DPE effects on tumor growth and angiogenesis are dependent on the inhibition of HIF-1α translation.Conclusions: We show that the in vivo DPE antitumor effect is associated with anti-inflammatory and antiangiogenic activities resulting from the downregulation of the HIF-1α/mPGEs-1/VEGF axis. Clin Cancer Res; 16(16); 4207-16. ©2010 AACR.

show abstract

NS398 reduces hypoxia‐inducible factor (HIF)‐1α and HIF‐1 activity: Multiple‐level effects involving cyclooxygenase‐2 dependent and independent mechanisms

Cited by 52 publications

References 66 publications

Apoptotic Effects of Etodolac in Breast Cancer Cell Cultures

Apoptotic Effects of Etodolac in Breast Cancer Cell Cultures

Coagulation-Mediated Hypoxia and Neutrophil-Dependent Hepatic Injury in Rats Given Lipopolysaccharide and Ranitidine

Inhibition of Hypoxia Inducible Factor-1α by Dihydroxyphenylethanol, a Product from Olive Oil, Blocks Microsomal Prostaglandin-E Synthase-1/Vascular Endothelial Growth Factor Expression and Reduces Tumor Angiogenesis

Contact Info

Product

Resources

About