Nitric Oxide Synthase Inhibition Promotes Carcinogen-Induced Preneoplastic Changes in the Colon of Rats

Schleiffer, R.; Duranton, B; Gossé, Francine; Bergmann, Christian; Raul, Françis

doi:10.1006/niox.2000.0310

Cited by 22 publications

(10 citation statements)

References 42 publications

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“…Levels of iNOS and eNOS are reported to be elevated in carcinoma tissue in response to azoxymethane, and similar observations on iNOS in human colorectal cancer have been made (36), but increased eNOS has also been correlated with improved survival in colorectal cancer (37). Inhibitors of iNOS have been observed to reduce ACF levels in the rat/azoxymethane model (38), but in one report in this model, a nonspecific NOS inhibitor increased ACF levels (39). In the …”

Section: Nos No and Colorectal Cancermentioning

confidence: 67%

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo

Hagos

Carroll²,

Kouznetsova³

et al. 2007

Molecular Cancer Therapeutics

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Chemopreventive agents in colorectal cancer possess either antiproliferative or anti-inflammatory actions. Nonsteroidal anti-inflammatory drugs (NSAID) and cyclooxygenase-2 inhibitors have shown promise, but are compromised by side effects. Nitric oxide donor NSAIDs are organic nitrates conjugated via a labile linker to an NSAID, originally designed for use in pain relief, that have shown efficacy in colorectal cancer chemoprevention. The NO chimera, GT-094, is a novel nitrate containing an NSAID and disulfide pharmacophores, a lead compound for the design of agents specifically for colorectal cancer. GT-094 is the first nitrate reported to reduce aberrant crypt foci (by 45%) when administered after carcinogen in the standard azoxymethane rat model of colorectal cancer. Analysis of proximal and distal colon tissue from 8-and 28-week rat/azoxymethane studies showed that GT-094 treatment reduced colon crypt proliferation by 30% to 69%, reduced inducible NO synthase (iNOS) levels by 33% to 67%, reduced poly(ADP-ribose)polymerase-1 expression and cleavage 2-to 4-fold, and elevated levels of p27 in the distal colon 3-fold. Studies in cancer cell cultures recapitulated actions of GT-094: antiproliferative activity and transient G 2 -M phase cell cycle block were measured in Caco-2 cells; apoptotic activity was examined but not observed; anti-inflammatory activity was seen in the inhibition of up-regulation of iNOS and endogenous NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. In summary, antiproliferative, anti-inflammatory, and cytoprotective activity observed in vivo and in vitro support GT-094 as a lead compound for the design of NO chimeras for colorectal cancer chemoprevention. [Mol Cancer Ther 2007;6(8):2230 -9]

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Section: Nos No and Colorectal Cancermentioning

confidence: 67%

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo

Hagos

Carroll²,

Kouznetsova³

et al. 2007

Molecular Cancer Therapeutics

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“…3) Some agents might have been dropped from Tables 1 and 2, if negative studies had also been taken into account and if mean potencies had been calculated for each agent. For instance, a specific nitric oxide synthase inhibitor prevents colon carcinogenesis (147) but can also promote carcinogenesis (299). Similarly, many agents shown here as preventive did enhance carcinogenesis in other rat studies (e.g., β-sitosterol, benzyl-and phenyl-hexylisothiocyanates, calcium, cellulose, diallyl sulfide, folic acid, genistein, germ-free status, glucarate, pectin, quercetin, resistant starch, rutin, selenium, tea extracts, vegetables-and-fruits mixture, and vitamin D 3 ).…”

Section: Discussionmentioning

confidence: 99%

Most Effective Colon Cancer Chemopreventive Agents in Rats: A Systematic Review of Aberrant Crypt Foci and Tumor Data, Ranked by Potency

Corpet¹,

Taché²

2002

Nutrition and Cancer

193

145

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Potential chemopreventive agents for colorectal cancer are assessed in rodents. We speculated that the magnitude of the effect is meaningful and ranked all published agents according to their potency. Data were gathered systematically from 137 articles with the aberrant crypt foci (ACF) end point and from 146 articles with the tumor end point. The potency of each agent to reduce the number of ACF is listed in one table and the potency of each agent to reduce the tumor incidence in another table. Both tables are shown in this review and on a website with sorting abilities (http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html). Potency was estimated as the ratio of the value in control rats to the value in treated rats. From each article, only the most potent agent was kept, except in articles reporting the effect of more than seven agents. Among the 186 agents in the ACF table, the median agent reduced the number of ACF by one-half. The most potent agents to reduce azoxymethane-induced ACF were Pluronic, polyethylene glycol, perilla oil with beta-carotene, and sulindac sulfide. Among the 160 agents in the tumor table, the median agent reduced the tumor incidence in rats by one-half. The most potent agents to reduce the incidence of azoxymethane-induced tumors were celecoxib, a protease inhibitor from soy, difluoromethylornithine with piroxicam, polyethylene glycol, and a thiosulfonate. For the 57 agents present in both tables, a significant correlation (r) was found between the potencies against ACF and tumors (r = 0.45, P < 0.001); without celecoxib, a major outlying point in the correlation, r = 0.68 (P < 0.001, n = 56). In conclusion, this review gathers most known chemopreventive agents, ranks the most promising agents against colon carcinogenesis in rats or mice, and further supports the use of ACF as a surrogate end point for tumors in rats.

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“…NO enhances the activity and expression of COX-2 in a variety of cell types [112]. Overall, these data suggest that the rate of development of adenoma, adenocarcinoma [91,113] and adenomatous polyps [34] is significantly decreased with l -NAME and iNOS-specific inhibitors (Table 2). …”

Section: Inos Selective Inhibitors and No-releasing Donors In Cancermentioning

confidence: 95%

iNOS-Selective Inhibitors For Cancer Prevention: Promise And Progress

Janakiram

Rao

2012

Future Med. Chem.

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Nitric oxide (NO) is involved in various physiological functions and its role in tumorigenesis has been well studied. A large majority of human and experimental tumors appear to progress owing to NO resulting from iNOS, further stimulated by proinflammatory cytokines. Conversely, in some cases, NO is associated with induction of apoptosis and tumor regression. This dichotomy of NO is largely explained by the complexity of signaling pathways in tumor cells, which respond to NO very differently depending on its concentration. In addition, NO alters many signaling pathways through chemical modifications, such as the addition of S-nitrosothiols and nitrosotyrosine to target proteins altering various biological pathways. Hence, iNOS inhibitors are designed and developed to inhibit various organ site cancers including the colon. Here, we review iNOS expression, generation of NO, involvement of NO in altering signaling pathways, and iNOS select inhibitors and their possible use for the prevention and treatment of various cancers.

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Nitric Oxide Synthase Inhibition Promotes Carcinogen-Induced Preneoplastic Changes in the Colon of Rats

Cited by 22 publications

References 42 publications

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo

Colon cancer chemoprevention by a novel NO chimera that shows anti-inflammatory and antiproliferative activity in vitro and in vivo

Most Effective Colon Cancer Chemopreventive Agents in Rats: A Systematic Review of Aberrant Crypt Foci and Tumor Data, Ranked by Potency

iNOS-Selective Inhibitors For Cancer Prevention: Promise And Progress

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