The Role of NAG-1/GDF15 in the Inhibition of Intestinal Polyps in <i>APC</i>/<i>Min</i> Mice by Sulindac

Wang, Xingya; Kingsley, Philip J.; Marnett, L.J.; Eling, Thomas E.

doi:10.1158/1940-6207.capr-10-0196

Cited by 22 publications

(23 citation statements)

References 38 publications

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“…Although the precise biological functions of NAG-1 are poorly understood, it is a member of the TGF-β superfamily that exhibits pro-apoptotic and anti-tumorigenic activity in animal and cell culture models (96). A recent study by Wang and colleagues found that NAG-1 is strongly induced in the liver of Min mice after sulindac treatment suggesting that NAG-1 induction may contribute to the tumor inhibitory effects of sulindac (97). …”

Section: Molecular Targetsmentioning

confidence: 99%

NSAIDs Inhibit Tumorigenesis, but How?

Gurpinar

Grizzle

Piazza

2014

Clinical Cancer Research

191

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: Molecular Targetsmentioning

confidence: 99%

NSAIDs Inhibit Tumorigenesis, but How?

Gurpinar

Grizzle

Piazza

2014

Clinical Cancer Research

191

135

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“…Evaluation by the same group of several sulindac derivatives [des-methyl (DM)-sulindac sulfide and its prodrug DM-sulindac] that do not inhibit COX-2 activity revealed that only sulindac significantly inhibited tumor formation in APC/Min mice (Wang et al, 2011). This was attributed to conversion of DM-sulindac to DM-sulindac sulfide (active form), which was less efficient than the conversion of sulindac to its active form, sulindac sulfide, in the mice.…”

Section: Evolving Role Of Nsaids In Colon Cancer Preventionmentioning

confidence: 99%

The Evolving Role of Nonsteroidal Anti-Inflammatory Drugs in Colon Cancer Prevention: A Cause for Optimism

Rigas

Tsioulias

2015

J Pharmacol Exp Ther

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Colorectal cancer (CRC) is a serious yet preventable disease. The low acceptance and cost of colonoscopy as a screening method for CRC make chemoprevention an important option. Nonsteroidal anti-inflammatory drugs (NSAIDs), not currently recommended for CRC prevention, have the potential to evolve into the agents of choice for this indication. Here, we discuss the promise and challenge of NSAIDs for this chemopreventive application. Multiple epidemiologic studies, randomized clinical trials (RCTs) of sporadic colorectal polyp recurrence, RCTs in patients with hereditary colorectal cancer syndromes, and pooled analyses of cardiovascular-prevention RCTs linked to cancer outcomes have firmly established the ability of conventional NSAIDs to prevent CRC. NSAIDs, however, are seriously limited by their toxicity, which can become cumulative with their long-term administration for chemoprevention, whereas drug interactions in vulnerable elderly patients compound their safety. Newer, chemically modified NSAIDs offer the hope of enhanced efficacy and safety. Recent work also indicates that targeting earlier stages of colorectal carcinogenesis, such as the lower complexity aberrant crypt foci, is a promising approach that may only require relatively short use of chemopreventive agents. Drug combination approaches exemplified by sulindac plus difluoromethylornithine appear very efficacious. Identification of those at risk or most likely to benefit from a given intervention using predictive biomarkers may usher in personalized chemoprevention. Agents that offer simultaneous chemoprevention of diseases in addition to CRC, e.g., cardiovascular and/or neurodegenerative diseases, may have a much greater potential for a broad clinical application.

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“…Sulindac inhibited polyp development in the APC/ Min mice, whereas DM-sulindac did not. Pharmacokinetic analysis showed sulindac was effectively converted to sulindac sulfide, the active metabolite, whereas DM-sulindac was rapidly excreted and not efficiently converted to the active DM-sulindac sulfide metabolite [116]. Further analysis of NAG-1 expression after sulindac treatment provided some clue as to the contribution of NAG-1 induction in sulindac-induced tumor inhibition in this study.…”

Section: Nag-1/gdf15mentioning

confidence: 79%

“…Feeding C57/BL6 mice sulindac induced mNAG-1 expression in liver and colon tissues [97, 116]. Indomethacin treatment has been shown to induce the expression of NAG-1 mRNA level in human sinonasal cancer cell AMC-HN5 xenograft tumors at a dose-dependent manner.…”

Section: Nag-1/gdf15mentioning

confidence: 99%

“…A number of sulindac derivatives (both sulfides and sulfoxides) were synthesized that lack of COX inhibitory activity to use as tools to study COX-2-independent mechanisms of NSAIDs. Two sulindac des-methyl (DM) analogues (DM-sulindac and DM-sulindac sulfide) devoid of COX activity induced NAG-1 expression in HCT-116 cells and the mouse rectal cancer cell line CMT93 [116]. Sulindac inhibited polyp development in the APC/ Min mice, whereas DM-sulindac did not.…”

Section: Nag-1/gdf15mentioning

confidence: 99%

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

Wang

Baek

Eling

2011

Cancer Metastasis Rev

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Inflammation is an important contributor to the development and progression of human cancers. Inflammatory lipid metabolites, prostaglandins, formed from arachidonic acid by prostaglandin H synthases commonly called cyclooxygenases (COXs) bind to specific receptors that activate signaling pathways driving the development and progression of tumors. Inhibitors of prostaglandin formation, COX inhibitors, or nonsteroidal anti-inflammatory drugs (NSAIDs) are well documented as agents that inhibit tumor growth and with long-term use prevent tumor development. NSAIDs also alter gene expression independent of COX inhibition and these changes in gene expression also appear to contribute to the anti-tumorigenic activity of these drugs. Many NSAIDs, as illustrated by sulindac sulfide, alter gene expressions by altering the expression or phosphorylation status of the transcription factors specificity protein 1 and early growth response-1 with the balance between these two events resulting in increases or decreases in specific target genes. In this review, we have summarized and discussed the various genes altered by this mechanism after NSAID treatment and how these changes in expression relate to the anti-tumorigenic activity. A major focus of the review is on NSAID-activated gene (NAG-1) or growth differentiation factor 15. This unique member of the TGF-β superfamily is highly induced by NSAIDs and numerous drugs and chemicals with anti-tumorigenic activities. Investigations with a transgenic mouse expressing the human NAG-1 suggest it acts to suppress tumor development in several mouse models of cancer. The biochemistry and biology of NAG-1 were discussed as potential contributor to cancer prevention by COX inhibitors.

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The Role of NAG-1/GDF15 in the Inhibition of Intestinal Polyps in APC/Min Mice by Sulindac

Cited by 22 publications

References 38 publications

NSAIDs Inhibit Tumorigenesis, but How?

NSAIDs Inhibit Tumorigenesis, but How?

The Evolving Role of Nonsteroidal Anti-Inflammatory Drugs in Colon Cancer Prevention: A Cause for Optimism

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

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