NO-releasing NSAIDs suppress NF-κB signaling in vitro and in vivo through S-nitrosylation

Chattopadhyay, Matangini; Goswami, Satindra; Rodes, Deborah B.; Kodela, Ravinder; Velázquez, Carlos; Boring, Daniel; Crowell, James A.; Kashfi, Khosrow

doi:10.1016/j.canlet.2010.07.006

Cited by 47 publications

(39 citation statements)

References 31 publications

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“…NO-acetylsalicylic acid (ASA) and NO-naproxen reduced NF-κB protein levels, activated caspase-3 and inhibited HT-29 human colon cancer cell growth. In rats, treatments with NO-ASA, NONO-ASA, and NO-naproxen led to S-nitrosylation of RelA sulfhydryl residues in the stomach tissue, increases in plasma TNF, and reductions in mucosal PGE2 levels [188]. Thus, NSAIDs might be used for cancer prevention or augment the efficacy of more conventional therapeutic approaches in developed cancer.…”

Section: Nf-κb and Gastric Cancer Therapymentioning

confidence: 99%

NF‐κB Signaling in Gastric Cancer

Sokolova

Naumann

2017

Toxins

175

122

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Gastric cancer is a leading cause of cancer death worldwide. Diet, obesity, smoking and chronic infections, especially with Helicobacter pylori, contribute to stomach cancer development. H. pylori possesses a variety of virulence factors including encoded factors from the cytotoxin-associated gene pathogenicity island (cagPAI) or vacuolating cytotoxin A (VacA). Most of the cagPAI-encoded products form a type 4 secretion system (T4SS), a pilus-like macromolecular transporter, which translocates CagA into the cytoplasm of the host cell. Only H. pylori strains carrying the cagPAI induce the transcription factor NF-κB, but CagA and VacA are dispensable for direct NF-κB activation. NF-κB-driven gene products include cytokines/chemokines, growth factors, anti-apoptotic factors, angiogenesis regulators and metalloproteinases. Many of the genes transcribed by NF-κB promote gastric carcinogenesis. Since it has been shown that chemotherapy-caused cellular stress could elicit activation of the survival factor NF-κB, which leads to acquisition of chemoresistance, the NF-κB system is recommended for therapeutic targeting. Research is motivated for further search of predisposing conditions, diagnostic markers and efficient drugs to improve significantly the overall survival of patients. In this review, we provide an overview about mechanisms and consequences of NF-κB activation in gastric mucosa in order to understand the role of NF-κB in gastric carcinogenesis.

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Section: Nf-κb and Gastric Cancer Therapymentioning

confidence: 99%

NF‐κB Signaling in Gastric Cancer

Sokolova

Naumann

2017

Toxins

175

122

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“…In fact, it has since been shown that structurally diverse NO-NSAIDs such as NO-aspirin and NO-naproxen can suppress NF- κ B signalling in cells via S-nitrosylation of the NF- κ B transcription factor. This redox-signalling mechanism is mediated by the released NO group which, on binding to the p65 monomer of NF- κ B, impairs the transcription factor's ability to bind to DNA [57]. The redox-induced inhibition of NF- κ B signalling is thought also to partly mediate the growth inhibitory effect (including apoptosis, cell cycle arrest, and inhibition of proliferation) of phospho-NSAIDs [19, 21, 111] and HS-NSAIDs in cancer cells [60].…”

Section: Cox-independent Nsaid-induced Apoptotic Cell Deathmentioning

confidence: 99%

The Proapoptotic Effect of Traditional and Novel Nonsteroidal Anti-Inflammatory Drugs in Mammalian and Yeast Cells

Farrugia

Balzan

2013

Oxidative Medicine and Cellular Longevity

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Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used to treat pain, fever, and inflammation. However, mounting evidence shows that NSAIDs, such as aspirin, have very promising antineoplastic properties. The chemopreventive, antiproliferative behaviour of NSAIDs has been associated with both their inactivation of cyclooxygenases (COX) and their ability to induce apoptosis via pathways that are largely COX-independent. In this review, the various proapoptotic pathways induced by traditional and novel NSAIDs such as phospho-NSAIDs, hydrogen sulfide-releasing NSAIDs and nitric oxide-releasing NSAIDs in mammalian cell lines are discussed, as well as the proapoptotic effects of NSAIDs on budding yeast which retains the hallmarks of mammalian apoptosis. The significance of these mechanisms in terms of the role of NSAIDs in effective cancer prevention is considered.

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“…Akt1 is also nitrosylated at the residue C224 and is inactivated under pathogenesis of iNOS and/or oxidative stress-involved insulin resistance [14]. The p65, an important component of the NFκB pathway, is also reported as being regulated by nitrosylation and impairs its ability to bind NFκB consensus binding site(s) in promoters of NFκB regulated genes [15], [16], [33], [34].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Therapeutic Potential of a Nitrosylating Agent in the Treatment of Ovarian Cancer

et al. 2014

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This study examines the role of s-nitrosylation in the growth of ovarian cancer using cell culture based and in vivo approaches. Using the nitrosylating agent, S-nitrosoglutathione (GSNO), a physiological nitric oxide molecule, we show that GSNO treatment inhibited proliferation of chemoresponsive and chemoresistant ovarian cancer cell lines (A2780, C200, SKVO3, ID8, OVCAR3, OVCAR4, OVCAR5, OVCAR7, OVCAR8, OVCAR10, PE01 and PE04) in a dose dependent manner. GSNO treatment abrogated growth factor (HB-EGF) induced signal transduction including phosphorylation of Akt, p42/44 and STAT3, which are known to play critical roles in ovarian cancer growth and progression. To examine the therapeutic potential of GSNO in vivo, nude mice bearing intra-peritoneal xenografts of human A2780 ovarian carcinoma cell line (2×106) were orally administered GSNO at the dose of 1 mg/kg body weight. Daily oral administration of GSNO significantly attenuated tumor mass (p<0.001) in the peritoneal cavity compared to vehicle (phosphate buffered saline) treated group at 4 weeks. GSNO also potentiated cisplatin mediated tumor toxicity in an A2780 ovarian carcinoma nude mouse model. GSNO’s nitrosylating ability was reflected in the induced nitrosylation of various known proteins including NFκB p65, Akt and EGFR. As a novel finding, we observed that GSNO also induced nitrosylation with inverse relationship at tyrosine 705 phosphorylation of STAT3, an established player in chemoresistance and cell proliferation in ovarian cancer and in cancer in general. Overall, our study underlines the significance of S-nitrosylation of key cancer promoting proteins in modulating ovarian cancer and proposes the therapeutic potential of nitrosylating agents (like GSNO) for the treatment of ovarian cancer alone or in combination with chemotherapeutic drugs.

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NO-releasing NSAIDs suppress NF-κB signaling in vitro and in vivo through S-nitrosylation

Cited by 47 publications

References 31 publications

NF‐κB Signaling in Gastric Cancer

NF‐κB Signaling in Gastric Cancer

The Proapoptotic Effect of Traditional and Novel Nonsteroidal Anti-Inflammatory Drugs in Mammalian and Yeast Cells

Preclinical Therapeutic Potential of a Nitrosylating Agent in the Treatment of Ovarian Cancer

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