COX inhibitors directly alter gene expression: role in cancer prevention?

Wang, Xingya; Baek, Seung Joon; Eling, Thomas E.

doi:10.1007/s10555-011-9301-4

Cited by 34 publications

(37 citation statements)

References 115 publications

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“…Inhibition of COX is generally thought to be the primary mechanism responsible for their antineoplastic activity, although numerous studies have concluded that alternative targets may be involved, as reviewed previously (2–4). Given that the use of NSAIDs for cancer chemoprevention is limited by COX-dependent toxicities, identifying the relevant targets that mediate their antitumor properties provides an opportunity to develop safer and more efficacious derivatives, or new chemical entities.…”

Section: Introductionmentioning

confidence: 96%

NSAIDs Inhibit Tumorigenesis, but How?

Gurpinar

Grizzle

Piazza

2014

Clinical Cancer Research

189

135

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Numerous epidemiological studies have reported that the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a significant decrease in cancer incidence and delayed progression of malignant disease. The use of NSAIDs has also been linked with reduced risk from cancer-related mortality and distant metastasis. Certain prescription strength NSAIDs, such as sulindac, have been shown to cause regression of precancerous lesions. Unfortunately, the extended use of NSAIDs for chemoprevention results in potentially fatal side effects related to their cyclooxygenase (COX)-inhibitory activity and suppression of prostaglandin synthesis. While the basis for the tumor growth-inhibitory activity of NSAIDs likely involves multiple effects on tumor cells and their microenvironment, numerous investigators have concluded that the underlying mechanism is not completely explained by COX inhibition. It may therefore be possible to develop safer and more efficacious drugs by targeting such COX-independent mechanisms. NSAID derivatives or metabolites that lack COX-inhibitory activity, but retain or have improved anticancer activity support this possibility. Experimental studies suggest that apoptosis induction and suppression of β-catenin-dependent transcription are important aspects of their antineoplastic activity. Studies show that the latter involves phosphodiesterase inhibition and the elevation of intracellular cyclic GMP levels. Here, we review the evidence for COX-independent mechanisms and discuss progress towards identifying alternative targets and developing NSAID derivatives that lack COX-inhibitory activity but have improved antineoplastic properties.

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Section: Introductionmentioning

confidence: 96%

NSAIDs Inhibit Tumorigenesis, but How?

Gurpinar

Grizzle

Piazza

2014

Clinical Cancer Research

189

135

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“…NAG-1 is also known as macrophage inhibitory cytokine-1, placental transforming growth factor-β, prostate-derived factor, placental bone morphogenetic protein, or growth differentiation factor-15 (GDF-15) [6,7]. NAG-1 is synthesized as a 308-amino acid pro-peptide and secreted as a mature protein after proteolytic cleavage [6,7,8,9,10]. The secreted form is present in the blood of humans and media of cultured cells expressing NAG-1 [9].…”

Section: Introductionmentioning

confidence: 99%

“…NAG-1 is synthesized as a 308-amino acid pro-peptide and secreted as a mature protein after proteolytic cleavage [6,7,8,9,10]. The secreted form is present in the blood of humans and media of cultured cells expressing NAG-1 [9]. Both the pro-form and secreted form are likely to play central roles in the biological activity of NAG-1 [6,7,9,10].…”

Section: Introductionmentioning

confidence: 99%

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Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells

Shimizu

Kadowaki

Yoshioka

et al. 2013

Biochemical and Biophysical Research Communications

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The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) is regulated by the p53 and Egr-1 tumor suppressor pathways. Many anti-cancer drugs and chemicals induce NAG-1 expression, but the mechanisms are not fully understood. Transgenic mice expressing human NAG-1 are resistant to intestinal and prostate cancer, suggesting that NAG-1 is a tumor suppressor. Proteasome inhibitors exhibit anti-glioblastoma activities in preclinical studies. Here, we show that the proteasome inhibitors MG132 and bortezomib induced NAG-1 expression and secretion in glioblastoma cells. MG132 increased NAG-1 expression through transcriptional and post-transcriptional mechanisms. At the transcriptional level, the induction of NAG-1 required the −133 to +41 bp region of the promoter. At post-transcriptional levels, MG132 stabilized NAG-1 mRNA by increasing the half-life from 1.5 h to > 8 h. Because of the dramatic increase in mRNA stability, this is likely the major contributor to MG132-mediated NAG-1 induction. Further probing into the mechanism revealed that MG132 increased phosphorylation of the p38 MAPK pathway. Consequently, inhibiting p38 phosphorylation blocked activation of the NAG-1 promoter and decreased mRNA stability, indicating that p38 MAPK activation mediates both MG132-dependent promoter activation and mRNA stabilization of NAG-1. We propose that the induction of NAG-1 by p38 MAPK is a potential contributor to the anti-glioblastoma activity of proteasome inhibitors.

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“…These side effects have been attributed to the inhibition of COX activity, with several studies implicating a COX-dependent mechanism. [8][9][10] Mitochondria have been the subject of recent research as a principal target of NSAID-induced toxicity. [11][12][13][14][15][16] Fenamic acid is an aromatic amino acid that is also called N-phenylanthranilic acid (NPA).…”

mentioning

confidence: 99%

Effect of <i>N</i>-Phenylanthranilic Acid Scaffold Nonsteroidal Anti-inflammatory Drugs on the Mitochondrial Permeability Transition

Tatematsu

Hayashi

Taguchi

et al. 2016

Biological & Pharmaceutical Bulletin

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Hepatotoxicity is a known side effect of nonsteroidal anti-inflammatory drugs (NSAIDs). In the present study, the effects of N-phenylanthranilic acid (NPA) scaffold NSAIDs on rat liver mitochondria were examined. Mefenamic acid (MEF, 200 µM) induced mitochondrial swelling, which was inorganic phosphate (Pi)-dependent and suppressed by cyclosporin A (CsA, 2.5 µM), similar to calcium-induced swelling. Mitochondrial swelling was also observed following the addition of 200 µM flufenamic acid (FLU), meclofenamic acid (MCL), and tolfenamic acid (TOL). Less swelling was observed with the addition of 200 µM diclofenac (DIC) or NPA. Diphenylamine (DPA)-induced swelling occurred in a Pi-independent manner and was not sensitive to CsA. The mechanism by which DPA interacted with the mitochondrial inner membrane differed from those of the other NPA scaffold NSAIDs. The addition of 50 µM MEF, MCL, TOL, and FLU had uncoupling effects in mitochondrial inner membrane. These NSAIDs dose-dependently obstructed electron transport in the respiratory chain. NSAIDs are known to have various dynamic structures, and the solvation free energies (dGWs: an index of stereo-hydrophobicity) of the conformers obtained were determined using a molecular orbital analysis. The relationship between the dynamic structures and swelling induced by NPA scaffold NSAIDs was also examined.

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COX inhibitors directly alter gene expression: role in cancer prevention?

Cited by 34 publications

References 115 publications

NSAIDs Inhibit Tumorigenesis, but How?

NSAIDs Inhibit Tumorigenesis, but How?

Proteasome inhibitor MG132 induces NAG-1/GDF15 expression through the p38 MAPK pathway in glioblastoma cells

Effect of <i>N</i>-Phenylanthranilic Acid Scaffold Nonsteroidal Anti-inflammatory Drugs on the Mitochondrial Permeability Transition

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