INVITED REVIEW
Nitric oxide in gastrointestinal epithelial
cell carcinogenesis: linking inflammation to oncogenesis
Meeta
Jaiswal,
Nicholas F.
LaRusso, and
Gregory J.
Gores
Center for Basic Research in Digestive Diseases, Division of
Gastroenterology and Hepatology, Mayo Clinic, Foundation, and
Medical School, Rochester, Minnesota 55905
 |
ABSTRACT |
Chronic inflammation of
gastrointestinal tissues is a well-recognized risk factor for the
development of epithelial cell-derived malignancies. Although the
inflammatory mediators linking chronic inflammation to carcinogenesis
are numerous, current information suggests that nitric oxide (NO)
contributes to carcinogenesis during chronic inflammation. Inducible
nitric oxide synthase (iNOS), expressed by both macrophages and
epithelial cells during inflammation, generates the bioreactive
molecule NO. In addition to causing DNA lesions, NO can directly
interact with proteins by nitrosylation and nitosation reactions. The
consequences of protein damage by NO appear to be procarcinogenic. For
example, NO inhibits DNA repair enzymes such as human
8-oxodeoxyguanosine DNA glycosylase 1 and blocks apoptosis via
nitrosylation of caspases. These cellular events permit DNA damage to
accumulate, which is required for the numerous mutations necessary for
development of invasive cancer. NO also promotes cancer progression by
functioning as an angiogenesis factor. Strategies to inhibit NO
generation during chronic inflammation or to scavenge reactive nitrogen
species may prove useful in decreasing the risk of cancer development
in chronic inflammatory gastrointestinal diseases.
apoptosis; cytokines; oxidative DNA damage; DNA repair; p53
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INTRODUCTION |
GASTROINTESTINALLY DERIVED epithelial
cell malignancies are common afflictions in the western world. Although
many of these cancers arise de novo without an identifiable
predisposing disease process, chronic inflammation of gastrointestinal
epithelia unequivocally predisposes to the development of cancers. For
example, chronic esophagitis, gastritis, pancreatitis, hepatitis,
cholangitis, and colitis are all known risk factors for cancers of the
esophagus, stomach, pancreas, liver and biliary tract, and colon,
respectively (16, 44, 52, 84). Although considerable
information is now available on the genetic and epigenetic changes
contributing to these cancers, the mechanisms by which chronic
inflammation contributes to these genetic alterations has not been
adequately explored. Insight into the mechanisms linking chronic
inflammation to gastrointestinal epithelial cell cancers may help in
the development of treatment strategies for reducing malignant
transformation in these inflammatory diseases. Moreover, information on
the inflammatory mediators contributing to cancer development may also
help identify new mechanisms of carcinogenesis [e.g., cyclooxygenase-2
(COX-2) and colon cancer] (69, 99).
Generation of nitric oxide (NO) by inducible nitric oxide synthase
(iNOS) is a cardinal feature of inflamed tissues including those of the
gastrointestinal tract (37, 40). iNOS overexpression with
high levels of NO generation provides a plausible link between inflammation and cancer initiation, progression, and promotion (Fig.
1). Indeed, there is substantial evidence
implicating NO in cancer as an endogenous mutagen (127),
an angiogenesis factor (43), an enhancer of protooncogene
expression (3), and an inhibitor of apoptosis
(59). Several human gastrointestinal neoplasms express
iNOS including gastric cancer (86), colonic adenomas
(100), Barrett's esophagus and associated adenocarcinomas (73), hepatocellular carcinoma (84), and
cholangiocarcinoma (33, 40) (Fig.
2). These observations suggest that iNOS
may play a fundamental role in the initiation and promotion/progression of cancers arising within a background of inflammation. Therefore, it
is both timely and topical to review the role of iNOS-generated NO in
carcinogenesis of gastrointestinal epithelial cells.

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Fig. 1.
Roles of nitric oxide (NO) in carcinogenesis. NO has been
implicated in modulating several events involved in malignant
transformation and cancer promotion/progression. NO can directly damage
DNA, inhibit DNA repair, block apoptosis, and enhance oncogene
expression. NO modulates transcription factors, especially
redox-sensitive and zinc finger motifs containing transcription
factors. NO has also been found to contribute to angiogenesis.
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Fig. 2.
Inducible nitric oxide synthase (iNOS) expression in
response to inflammatory diseases in the gastrointestinal tract. There
are emerging clinical data showing that chronic inflammatory conditions
along the digestive tract, liver, and pancreas have increased
expression of iNOS. Moreover, expression of iNOS is retained by the
associated cancers, suggesting that iNOS is important in the
development and expression of these malignancies. PSC, primary
sclerosing cholangitis.
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NITRIC OXIDE SYNTHASES AND NITRIC OXIDE |
NO is a 30-kDa gaseous biological mediator synthesized in
mammalian cells by a family of three NOS isoforms. The human
genes for NOS are characterized as neuronal or nNOS (NOS1), endothelial or eNOS (NOS3), and iNOS (NOS2) (23). NOS catalyzes the
conversion of the terminal guanidino nitrogen of the amino acid
L-arginine to form NO plus citrulline in a complex reaction
involving molecular oxygen and NADPH as cosubstrates with enzyme-bound
heme, FAD, flavin mononucleotide (FMN), and tetrahydrobiopterin
(BH4) as cofactors (5, 110). The two
constitutive isoforms of NOS, eNOS, and nNOS, are controlled by calcium
fluxes and produce only nanomolar NO concentrations. In contrast, the
dimeric iNOS protein is permanently active and capable of generating
micromolar concentrations of NO on induction in the absence of changes
in cellular calcium (68, 72). The iNOS gene is under
transcriptional control of inflammatory cytokines and
lipopolysaccharides (25, 39, 79). The human iNOS gene was
first cloned from synergistic activation of tumor necrosis factor
(TNF)-
, interleukin (IL)-1
, and interferon (IFN-
) in
hepatocytes (24, 83). iNOS gene expression is regulated by
the transcription factors nuclear factor (NF)-
B, the Janus kinase
(JAK)-signal transducer and activator of transcription (STAT) pathway,
and c-Jun NH2-terminal kinase (JNK)-activator protein-1
(AP-1) pathways (103). The enzyme is downregulated by
steroids, transforming growth factor (TGF)-
, the heat shock response
element, p53, and NO itself (111). The complexity of iNOS
catalysis and its regulation is reflected in the broad range of
biological and cell/tissue-specific physiological and
pathophysiological functions of NO (6). Studies have shown
very little correlation between iNOS mRNA expression and enzyme
activity, suggesting a considerable degree of posttranscriptional
regulation. iNOS induction by cytokines and NF-
B likely accounts for
its ubiquitous expression and activity during inflammation.
 |
INOS EXPRESSION IN GASTROINTESTINAL EPITHELIA |
Almost every cell in the body has the capacity to express iNOS
(78). In inflamed gastrointestinal tissue, iNOS is richly expressed by infiltrating and resident activated macrophages (15, 78). The NO generated by activated macrophages may have
significant physiological benefits (82). For example, NO
produced by macrophage iNOS has important antimicrobial functions
(6, 119) and inhibits the growth of viruses
(45), parasites (27), and gram-positive organisms (35) that invade the gastrointestinal tract.
Although macrophage-derived NO appears to be important in innate
immunity, the high diffusion efficiency of NO makes it potentially
reach unintended targets (e.g., neighboring epithelial cells).
Inflammatory cytokines will also trigger iNOS expression by epithelial
cells (112). Indeed, iNOS has been identified in gastric
metaplasia of the esophagus (73), mucosal cells of the
stomach in chronic gastritis (66), hepatocytes in viral
hepatitis (65, 84), cholangiocytes in primary sclerosing
cholangitis (38), and colonocytes in inflammatory bowel
disease (100). In contrast to macrophage-generated NO,
epithelial cell NO has ready access to epithelial cell targets including those important in carcinogenesis. Thus the salutary effects
and potentially detrimental consequences of NO generation in
inflammation exist along a continuum related to the magnitude and
chronicity of NO exposure. This continuum of iNOS activity and NO
generation in immunoregulatory functions can be divided into three
stages: 1) under physiological conditions, normal to low
quantities of NO produced by constitutive and inducible NOS act as an
intracellular activation signal; 2) when NO production is
increased for longer periods of time via iNOS, NO functions as an
autocrine or paracrine immunoregulatory molecule; and 3) chronic and sustained generation of NO can be associated with direct
reactions between NO and cellular constituents and generation of
reactive nitrogen species. It is this latter condition that has been
postulated to play a pivotal role in carcinogenesis. This interplay is
exemplified in Helicobacter pylori infection of the stomach,
an infection well documented to be a risk factor for gastric cancer
(66, 121). In this process, H. pylori elicits a
host inflammatory response with iNOS generation of NO to potentially eradicate the organism. However, because of this bacterium's ability to persist, the inflammatory response becomes chronic and predisposes to cancer with persistence of iNOS expression by the malignancy (86).
 |
NO AND CELLULAR DNA AND PROTEIN DAMAGE |
The toxicity of NO during chronic inflammation occurs by two
chemical processes, 1) oxidation of NO with superoxide to
form peroxynitrite (ONOO
) and nitrosating species,
namely, NO
(nitrates), NO
(nitrites), and N2O3 (126),
referred to as reactive nitrogen oxide species (RNOS), and
2) direct reactions between proteins and NO by nitrosylation events.
NO can damage DNA through a variety of different mechanisms that may be
cell specific (107). Nitrosation of purines and
pyrimidines results in hydrolytic deamination of cytosine to uracil and
guanine to xanthine (81, 109). GC
AT and GC
CG
transitions (replacement of purine by pyrimidine base or vice versa)
are major mutations observed in naked DNA and human cells exposed to NO
(127). Sequence data of gene mutations from patients with
hepatocellular carcinoma and gastric carcinogenesis reveal the same GC
AT transitions (12, 121). N2O3
is a powerful electrophilic nitrosating agent that causes the formation
of carcinogens
N-nitroso compounds, DNA strand breaks, and
cross-linking of DNA (109). Peroxynitrite can also react
directly with DNA and lead to mutations and DNA strand breaks
(106). Besides deamination, NO and/or peroxynitrite can
cause DNA base oxidation measured as conversion of guanine to
8-nitroguanine and 8- oxoguanine (8-oxodG). H. pylori
infections in humans have been associated with an increased release of
8-oxoguanine in urine and the formation of nitrotyrosine in gastric
antral biopsies (66, 129). Acute hepatic injury and/or
cell necrosis was accompanied by significant induction of iNOS in the
liver and other organs with increased nitrosamine formation and release in human urine (92). In fact, increased endogenous
formation of nitrate and nitrosamines is recognized as a risk factor
for cholangiocarcinoma in humans infested with Opisthorchis
viverrini (94, 124) and for hepatocellular carcinoma
in cirrhosis patients (61).
NO can also directly nitrosylate susceptible thiol residues on
proteins, resulting in the loss of their catalytic activity (87). In many proteins, this is a reversible reaction, but
in proteins containing zinc, copper, or iron, the thiol nitrosylation results in irreversible ejection of the metal and denaturation of the
protein (58). The reaction of NO with iron-sulfur centers may also perpetuate radical reactions. NO and peroxynitrite react rapidly with iron-sulfur centers, and the resultant free iron may then
generate hydroxyl free radical-induced damage via Fenton chemistry
(125). Peroxynitrite and NO can oxidize protein and nonprotein thiols, protein sulfides, lipids, and low-density
lipoproteins (14, 85). 3-Nitrotyrosine is a stable marker
of oxidative protein damage by RNOS (93). The presence of
nitrotyrosine has been identified by immunohistochemistry in relation
to gut tissue subjected to chronic inflammation with increased iNOS
expression such as H. pylori gastritis (66),
primary sclerosing cholangitis (38), cholangiocarcinoma
(40), pancreatic cancer (122), and esophageal
squamous cell cancer (46). Thus there is ample evidence for the presence of reactive oxygen species and NO-mediated DNA and
protein damage in gastrointestinal epithelia during chronic inflammation.
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NO AND DNA REPAIR PROTEINS |
Although NO and reactive oxygen species can directly damage DNA,
mammalian cells have rich and complex mechanisms to repair the genome.
Several DNA repair processes are now recognized including base excision
repair (BER), nucleotide excision repair, transcription-coupled repair,
double strand break repair, and mismatch repair (Table 1; Refs. 20,
97, and 130). Accumulation of DNA damage during inflammation, therefore, represents the net result of both direct damage and ineffective repair. Unfortunately, DNA repair enzymes also
appear to be protein targets of NO and reactive oxygen species (102, 128). Thus iNOS-generated NO may give the cell a
double hit by both damaging the DNA and inhibiting its repair
processes. This effect of NO and its by-products may make NO one of the
pivotal mediators linking inflammation to carcinogenesis.
Several key DNA repair enzymes are inhibited by NO-mediated
nitrosylation of active site cysteine. The DNA repair enzymes with
vulnerable active site cysteine residues include 6-O-alkyl DNA transferase (56), foramidopyrimidine glycosylase
(54), xeroderma pigmentosum A protein (76),
and DNA ligases with active site lysine residues (60). We
recently demonstrated (40) that cytokine-mediated
induction of iNOS with NO production is associated with diminished
global DNA repair capacity in cholangiocarcinoma cell lines. Although
DNA oxidative lesions, the predominant mechanism of DNA damage in
inflammation, can be excised from DNA by multiple pathways, BER is
quantitatively the most important (41, 55). 8-oxodG, the
most abundant oxidative DNA lesion, is excised in humans by
8-oxodeoxyguanosine DNA glycosylase 1 (hOgg1) (51, 95,
131). This glycosylase contains critical thiol moieties in a
zinc finger at its active sites (91, 108). Our group has demonstrated that the hOgg1 repair enzyme is inhibited by NO and peroxynitrite generation because of formation of
S-nitrosylation at their active site cysteine residues and
ejection/loss of zinc (38, 40). This is a good example of
how iNOS overexpression due to inflammatory cytokines can be
mechanistically linked to accumulation of DNA damage resulting from
inhibition of a specific important DNA repair enzyme (Fig.
3).

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Fig. 3.
NO inhibits hOgg1 base excision repair activity. NO
causes oxidative DNA damage [e.g., 8-oxoguanine (8-oxodG)] and
potentiates the accumulation of the damage by inhibiting the repair
activity of its key repair enzyme, human 8-oxydeoxyguanosine DNA
glycosylase 1 (hOgg1). Unrepaired 8-oxodG causes GC to TA transitions
and is mutagenic.
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NO AND APOPTOSIS |
In addition to repairing damaged DNA, the organism has another
safeguard against cellular transformation, programmed cell death by a
process known as apoptosis (34, 104). DNA damage that cannot be repaired is a potent inducer of apoptosis
(53). For example, DNA-damaging drugs,
-radiation, and
ultraviolet light all trigger apoptosis by inducing DNA damage
(8). In these circumstances apoptosis is mediated
by activation of caspases, a family of cysteine proteases
(42). Caspase activation occurs by one of two broad
mechanisms, death receptors and/or mitochondrial cytochrome
c release (26, 67). The death receptor pathway is initiated by caspase-8, whereas the mitochondrial pathway is dependent on caspase-9. Both death receptor- and mitochondria-initiated apoptotic cascades involve the downstream caspases-3, -6, and -7, which execute the apoptotic program (Fig.
4) (118). Although either or
both pathways can be disrupted in established malignancies, dysregulation of the mitochondrial pathway appears to be very important
in cancer development and therapy (47). In this pathway, apoptotic signals are initiated by the release of cytochrome
c from mitochondria (34, 63). By inhibiting
caspase activity through S-nitosylation of the active site
cysteine, NO inhibits apoptosis in hepatocytes
(48), endothelial cells (10), and several
tumor cell lines (9, 63). Indeed, NO has been shown to
directly nitrosylate caspases-3, -8, and -9, resulting in their inactivation and inhibition of apoptosis (49, 50).
Studies have shown that prevention of NO protein damage induced by
intestinal ischemia-reperfusion can protect against
hypoxia-induced apoptosis in HT-29 colon carcinoma cells by
inhibiting cytochrome c release from the mitochondria
(34, 63, 64). In addition to the NOS isoforms described
above, mitochondria are also capable of generating NO, although the
mechanism responsible remains obscure (26). It is possible
that this mitochondria-derived NO is capable of inhibiting
apoptosis at the level of this organelle in addition to caspase
nitrosylation. Thus NO may inhibit apoptosis at several steps,
further allowing the DNA-damaged cell to survive.

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Fig. 4.
Inhibition of caspase activation by NO prevents
apoptosis. NO blocks both the death receptor and mitochondrial
pathways by nitrosylation of caspase-8 and caspases-9 and -3, respectively. The resultant failure of apoptosis allows the
survival of genetically altered cells and is thought to play a pivotal
role in carcinogenesis. Bid, BH3-interacting domain death
agonist.
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NO, P53, AND TUMORIGENESIS |
NO and reactive oxygen species generated during chronic
inflammation may initiate and enhance carcinogenesis in humans by the
biochemical interactions discussed above. Infection by bacteria (H. pylori), parasites (liver fluke helminthes), or viruses
(hepatitis B and C) and chronic tissue inflammation are recognized risk
factors in the etiology and development of cancers. The process of
carcinogenesis is a multistep process involving inactivation of tumor
suppressor genes and activation of oncogenes by either DNA mutations or
deletions. The DNA repair molecule p53 plays a important role in the
cellular response to DNA damage. As mentioned above, the NO-mediated
deamination of DNA causes GC
AT transitions. NO-induced DNA damage
results in upregulation of p53, an important trans-repressor
of iNOS expression in vivo, and attenuates NO production by a
regulatory negative feedback mechanism (3, 19). The p53
gene in many human cancers, including liver cancer from hepatitis B
(32) and H. pylori-associated gastric cancer
(121), has GC
AT transitions. These transitions occur mainly at CpG islands of the p53 gene and occur in a number of
human cancers, including colon, gastric, and hepatocellular cancers
(1, 28). NO production via iNOS may directly induce these
GC
AT mutations in p53, providing another molecular link between
chronic inflammation and cancer development. For example, a
relationship between p53 mutations and iNOS expression has been established in human colorectal cancer and several human carcinoma cell
lines (2, 37). Not only may NO contribute to the
development of p53 mutations, but the loss of repressor activity of the
mutated p53 would increase iNOS, resulting in enhanced cellular NO
generation, further DNA damage, and the development of additional
transforming mutations (Fig. 5).

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Fig. 5.
p53 and NO-mediated proliferation of malignant cells. The
tumor suppressor p53 gene is upregulated in response to increased
iNOS/NO generation with associated DNA damage. The upregulation of p53
inhibits iNOS expression and arrests the cell cycle, allowing repair to
be initiated. However, p53 in cancers (gastric, hepatocellular,
hereditary nonpolyposis colorectal cancer, etc.) is mutated. Mutated
p53, required in failure of this negative feedback loop, causes
enhanced iNOS expression, thereby aggravating the consequences of
enhanced chronic iNOS expression. RNOS, reactive nitrogen oxide
species.
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NO AND ANGIOGENESIS |
Because neovasculature is necessary for tumor growth and
immunohistochemical studies have indicated that iNOS is overexpressed in solid tumors (22), production of NO may promote tumor
growth by stimulating angiogenesis (43, 74), increasing
vascular permeability, and suppressing the immune response
(57). Angiogenesis is a complex, multistage process,
regulation of which requires release of vascular endothelial growth
factor (VEGF), angiogenin, adhesion molecules, and basic fibroblast
growth factors delivered by the tumor cells themselves, the
extracellular matrix, or incorporated macrophages (18).
Initial studies suggest that NO plays a central role in the angiogenic
cascade by demonstrating that VEGF released as a purified protein or
produced by tumor cells requires a functional NO/cGMP pathway within
the endothelial compartment to promote neovascular growth (22,
75, 135). Another mechanism by which NO may promote tumor growth
is by modulating the production of prostaglandins. NO activates COX-2
(98), which stimulates the production of proangiogenic
factors and prostaglandins that facilitate tumor growth by increasing
vascular permeability, and by concomitant inhibition of
apoptosis from enhanced Bcl-2 protein production (120). The use of iNOS inhibitors as antiangiogenesis
agents is now supported by several reports in the literature (reviewed in Ref. 116).
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NO, CHRONIC INFLAMMATION, AND THERAPEUTIC INTERVENTION |
The use of oxygen by aerobic organisms invariably results in the
formation of reactive oxygen species. Cells counterbalance prooxidants
with antioxidants. For example singlet oxygen and superoxide are
dismuted by Mn superoxide dismutase in the mitochondria and Cu/Zn
superoxide dismutase in the cytosol, and H2O2
is detoxified by glutathione peroxidase, a selenium enzyme, and by
catalases. Besides these defenses, the cell has other proteins
like thioredoxin, glutaredoxin, and thioltransferase that participate
in maintaining the equilibrium between prooxidant and antioxidant. In
addition, many small molecules such as
-tocopherol, ascorbate,
albumin, uric acid, and glutathione act as scavengers of reactive
oxygen species. Genetic stability is also maintained by the activity of
efficient DNA repair enzymes. However, during chronic inflammation, the
cell is bombarded with the accelerated and sustained production of
oxygen and nitrogen free radicals and ions that saturate the antioxidant capacity of the cell, inhibit DNA repair function and
programmed cell death, and are potentially carcinogenic. The recognition of the multifaceted role of NO in modulating mutagenesis in
chronic inflammatory diseases suggests several therapeutic approaches
(36, 77).
iNOS and its associated mediators have been targeted for therapeutic
intervention. The current potential strategies for intervention include
1) scavengers of NO and peroxynitrite, 2)
repression of iNOS expression by drugs, antisense technology, and p53,
and 3) inhibition of iNOS protein and its cofactors.
Carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) (132) and PTIO (29) are potent
scavengers for NO. Trolox (96), ebselen
(4) and Mn(III)tetrakis (4-benzoic acid) porphyrin
chloride (MnTBAP), a superoxide dismutase mimetic, (17)
have been used successfully to scavenge for peroxynitrite. The efficacy
of these scavengers in a malignant murine model has been gratifying
(30, 123). Curcumin (from Curcuma longa), a naturally occurring polyphenolic phytochemical, is in preclinical trial
for cancer chemoprevention. Curcumin inhibits activation of free
radical-activated transcription factors such as NF-
B and AP-1 and
reduces the production of proinflammatory cytokines such as TNF-
,
IL-1
, and IL-8. In addition to inhibiting cytokine-mediated activation of iNOS, curcumin has been shown to inhibit iNOS gene expression in mouse liver (11). Inhibition of gene
expression by hybridization of antisense oligonucleotides to the
transcripts also has therapeutic potential (13). An
antisense oligodeoxynucleotide to iNOS mRNA designed to inhibit
translation of iNOS was found to partially inhibit nitrite production
in cytokine-stimulated cells (115). Selective inhibitors
of iNOS that blocked iNOS dimerization and NO production both in vitro
and in vivo were identified in an encoded combinatorial chemical
library. These inhibitors were >1000-fold more potent than
substrate-based iNOS inhibitors such as 1400W (70).
Irreversible inhibition of iNOS was achieved by using flavoprotein
iodonium inhibitors that prevented the binding of cofactors NADPH, FMN,
and FAD (21). BH4, another essential cofactor
of iNOS, can be inhibited by N-acetylserotonin and dicumarol (101). iNOS isoform-selective substrate-based arginine
analog inhibitors can be exploited for therapeutic purposes because
arginine binding domains for the isoforms are different. Several
general analogs of arginine such as
NG-monomethyl-L-arginine
(L-NMMA) acetate and
L-N6-(1-iminoethyl) lysine
(L-NIL) are effective nonspecific inhibitors of iNOS.
1400W, a selective inhibitor of iNOS, inhibits the growth of solid
murine tumors expressing iNOS (117). Aminoguanidine and
mercaptoethylguanidine are inhibitors of iNOS and have
anti-inflammatory properties because they protect against
peroxynitrite-induced oxidative damage (105).
Chemopreventive approaches may include inhibition of iNOS expression
with tetracycline and minocycline (133, 134). Preclinical
animal studies involving iNOS inhibitors have been effective in chronic
colitis (88, 90). Expression of p53 in cancer cells
lacking this tumor suppressor gene can lead to cell apoptosis
or cycle arrest and may also inhibit the angiogenesis required for
tumor growth by decreasing iNOS expression. Studies have initiated the
use of adenoviral vectors for effective locoregional delivery and
transient overexpression of p53 and consequently effective p53 gene
therapy for cancer (80).
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SUMMARY |
The current literature suggests that NO is involved in many of the
pathophysiological processes linking inflammation to cancer development
and progression in the gastrointestinal tract. NO, generated by iNOS in
these disease states, is a reactive biomolecule. When the generation of
NO exceeds the antioxidant capacity of the cell, NO and its reactive
nitrogen oxide species are capable of damaging DNA and proteins. In
particular, NO-mediated nitrosylation of DNA repair proteins inhibits
their enzymatic activity, potentiating accumulation of DNA damage. NO
can also nitrosylate and inactivate the effector proteins of
apoptosis, especially caspases. Inhibition of caspases results
in dysregulation of apoptosis, further promoting malignant
transformation. Because it is associated with VEGF formation, NO can
also be considered an angiogenic factor, thereby promoting cancer
progression. These concepts provide a model to test the utility of iNOS
inhibitors and NO scavengers as chemopreventive agents to minimize the
risk of human cancers in these premalignant diseases. We encourage
these studies and await their results.
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ACKNOWLEDGEMENTS |
This work was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grants DK-59427 (G. J. Gores) and
DK-24031 (N. F. LaRusso) and by the Mayo Comprehensive Cancer Center, Rochester, MN (CA-15083).
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FOOTNOTES |
Address for reprint requests and other correspondence: G. J. Gores, Mayo Medical School, Clinic, and Foundation, Rochester, MN
55905 (E-mail: gores.Gregory{at}mayo.edu).
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