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Chronic Inflammation and Oxidative Stress as a Major Cause of Age- Related Diseases and Cancer

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Abstract

Chronic inflammation is a pathological condition characterized by continued active inflammation response and tissue destruction. Many of the immune cells including macrophages, neutrophils and eosinophils are involved directly or by production of inflammatory cytokine production in pathology of chronic inflammation. From literatures, it is appear that there is a general concept that chronic inflammation can be a major cause of cancers and express aging processes. Moreover, many studies suggest that chronic inflammation could have serious role in wide variety of age-related diseases including diabetes, cardiovascular and autoimmune diseases. Inflammatory process induces oxidative stress and reduces cellular antioxidant capacity. Overproduced free radicals react with cell membrane fatty acids and proteins impairing their function permanently. In addition, free radicals can lead to mutation and DNA damage that can be a predisposing factor for cancer and age-related disorders. This article reviews the antioxidant defense systems, free radicals production and their role in cancer and age related diseases and also some of the recent patent relevant to the field. Study of the role of free radicals in human diseases can help the investigators to consider the antioxidants as proper agents in preventive medicine, especially for cancer and aging processes.
Recent Patents on Inflammation & Allergy Drug Discovery 2009, 3, 73-80 73
1872-213X/09 $100.00+.00 © 2009 Bentham Science Publishers Ltd.
Chronic Inflammation and Oxidative Stress as a Major Cause of Age-
Related Diseases and Cancer
Nemat Khansari*, Yadollah Shakiba and Mahdi Mahmoudi
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
Received: August 1, 2008; Accepted: August 27, 2008; Revised: September 12, 2008
Abstract: Chronic inflammation is a pathological condition characterized by continued active inflammation response and
tissue destruction. Many of the immune cells including macrophages, neutrophils and eosinophils are involved directly or
by production of inflammatory cytokine production in pathology of chronic inflammation. From literatures, it is appear
that there is a general concept that chronic inflammation can be a major cause of cancers and express aging processes.
Moreover, many studies suggest that chronic inflammation could have serious role in wide variety of age-related diseases
including diabetes, cardiovascular and autoimmune diseases. Inflammatory process induces oxidative stress and reduces
cellular antioxidant capacity. Overproduced free radicals react with cell membrane fatty acids and proteins impairing their
function permanently. In addition, free radicals can lead to mutation and DNA damage that can be a predisposing factor
for cancer and age-related disorders.
This article reviews the antioxidant defense systems, free radicals production and their role in cancer and age related
diseases and also some of the recent patent relevant to the field. Study of the role of free radicals in human diseases can
help the investigators to consider the antioxidants as proper agents in preventive medicine, especially for cancer and aging
processes.
Keywords: Chronic inflammation, cancer, age-related diseases, free radicals, DNA damage, antioxidant, angiogenesis.
INTRODUCTION
Inflammation is a protective mechanism employed by
tissues against endogenous and exogenous antigens. The
relationship between chronic inflammation and many can-
cers has been recognized [1]. Chronic inflammation is a pro-
longed pathological condition characterized by mononuclear
immune cell infiltration [monocytes, macrophages,
lymphocytes, and plasma cells], tissue destruction and
fibrosis. However, chronic inflammation exerts its cellular
side effects mainly through excessive production of free
radicals and depletion of antioxidants [2]. Aging may be
defined as a progressive decline in the physiological
functions of an organism after the reproductive phase of its
life. The idea that, aging is the result of free radical damage,
is often credited to Denham Harman, who proposed this
theory based on this observation that, irradiation induces the
formation of free radicals, shortens life span, and produces
changes that resemble aging processes [3]. His work has
gradually triggered intense researches into understanding the
role of free radicals in biological systems. The main aim of
this review is to analyze the role of free radicals, which are
by products of chronic inflammation, in carcinogenesis and
aging.
GENERAL CONCEPTS OF FREE RADICALS
In the last two decades, there has been a considerable
amount of interest in the role of reactive oxygen species
(ROS) and reactive nitrogen species (RNS) in clinical
*Address correspondence to this author at the Professor of Immunology,
Department of Immunology, School of Medicine, Tehran University of
Medical Sciences, Tehran, Iran; Tel/Fax: +98-21-66419536;
E-mail: khansari@nematk.com
medicine. A free radical is defined as any chemical species
that contains unpaired electrons. This unpaired electron
usually produces a highly reactive free radical.
In biological systems, the most common source of free
radicals is oxygen.
The harmful effects and biological damage caused by
ROS and RNS is termed oxidative stress and nitrosative
stress [4]. Unfavorable side effects occur when there is an
imbalance between overproduction of ROS/RNS and
decrease of antioxidant molecules in body. Generally, ROS
and RNS play dual roles in body: deleterious and beneficial
effects [5]. Usually the beneficial effects of ROS involve
defense against microbial pathogens. This role occurs by low
concentration of these molecules. However, overproduction
of ROS or RNS can damage and inhibit the normal functions
of lipids, proteins and DNA. This effect is due to
intracellular reduction of O2 into ROS or free radicals, which
is toxic to cells and tissues [6].
ROS can be produced from both endogenous and
exogenous cellular substances. Potential endogenous sources
include mitochondria, cytochrome P450, peroxisomes, and
inflammatory cells activation [7]. Mitochondria generate
significant quantities of hydrogen peroxide and use ~90% of
cellular O2. During the mitochondrial process of reducing
oxygen for production of water, several short-lived inter-
mediates are produced, including superoxide (O2), hydrogen
peroxide (H2O2) and the hydroxyl radical [OH]. Superoxide
and hydroxyl radicals are toxic to cells. Cell destruction also
causes further free radical generation [6].
Additional endogenous sources of cellular reactive
oxygen species are neutrophils, eosinophils and macro-
phages. Activated macrophages initiate increase in oxygen
74 Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 Khansari et al.
uptake and give rise to a variety of reactive oxygen species,
including O2, nitric oxide (NO) and hydrogen H2O2 [8].
Liver macrophages {Kupffer cells} participate in free
radical-induced hepatotoxicity and liver cancer by producing
inflammatory cytokines [9]. Recent investigations suggest
that there is a direct relationship between Kupffer cells,
inflammatory cytokines, and liver tumor promotion [10].
In addition, intracellular formation of free radicals can
occur by environmental sources including ultraviolet light,
ionizing radiation, and pollutants such as paraquat and
ozone. All of these sources of free radicals, both enzymatic
and nonenzymatic, have the potential to inflict oxidative
damage on a wide range of biological macromolecules [11].
TARGETS OF FREE RADICALS
The cell membrane is one of the most susceptible sites to
ROS damage. Free radicals can react with cell membrane
fatty acids and form lipid peroxides. Lipid peroxides
accumulation can lead to production of carcinogenesis agents
like malondialdehyde [12]. Cell membrane damage via lipid
peroxidation can permanently impair fluidity and elasticity
of the membrane, which can lead to the cell rupture. These
changes are particularly significant in long-lived cells such
as neurons [13].
The proteins are another main targets for free radicals
attack. Overproduced radicals can react with protein
aminoacids to oxidize and cross-link them. Radical-protein
reactions can impair the function of important cellular and
extracellular proteins like enzymes and connective tissue
proteins permanently. Based on many investigations,
accumulation of tissue and cell damage is much higher in
aged individuals. In fact, it has been estimated that oxidized
protein in old animals may compose 30-50% of the total
cellular protein [14].
DNA is also highly susceptible to free radical attacks. An
oxygen radical interaction with DNA can break its strands or
delete a base. This DNA damage can be a lethal event for an
organism. The rate of DNA damage inflicted by free radicals
is considerably high; it is estimated that in average more than
10,000 oxidative hits occur each day in the DNA of a human
cell [15]. Although cellular repair system corrects much of
these damages, but the radical induced DNA lesion that
accumulate with age, can be an important etiology aging of
processes [6].
FREE RADICALS IN MITOCHONDRIA
Mitochondria are the main cellular organelles that are
involved in free radical production. Mitochondria consume
about 90% of the cellular oxygen and are the most
susceptible organelles to oxidative damage. Mitochondrial
DNA contains histone that is highly susceptible to reactive
oxygen damage. Moreover, mitochondria contain more than
100 different enzymes, involved in ATP production, which
continuously interact with free radicals. Decrease activity of
some of these enzymes during the aging process might be
due to the long time interaction of these enzymes with free
radicals. It has been estimated that the number of oxidative-
induced damages in mitochondrial DNA is ten times higher
than nuclear DNA. It has been shown that mitochondrial
DNA damage accumulates with age and can have an
important role in cellular aging too [15]. It should be also
noted that DNA repair is much less efficient in mitochondria
than in the nucleus [16].
The lack of equilibrium between free radical production
in mitochondria and anti-oxidant defense mechanisms in this
organelle may leads to leak of these harmful reactant to
cytoplasm or connective tissues, hence damaging tissues
and/or cells. Based on these facts, mitochondria can have a
very important intermediatory role in age-related tissue
degradation and aging processes [17].
DEFENSE MECHANISMS AGAINST FREE
RADICALS
In order to neutralizing the threat of free radicals to the
tissues and cells, a wide variety of antioxidant and repair
systems has been evolved. Defense mechanisms against
oxidative stress can be divided into: antioxidant, preventative
and repair mechanisms, and physical defenses. Many
enzymes participate in free radical neutralizing processes
include: glutathione peroxidase, superoxide dismutase
(SOD), and catalase. The non-enzymatic antioxidants that
participate in oxidative stress defense include: ascorbic acid
(Vitamin C), alpha-tocopherol (Vitamin E), glutathione
(GSH), carotenoids, and flavinoids. In the normal and
healthy cells, there is a precise balance between free radicals
production and the level of antioxidant molecules, but under
oxidative stress condition, the balance has been tilted
towards excessive of oxidative radicals.
It is well understood that reduced-glutathione is an
important cellular antioxidant molecule in the mitochondria
and cell nucleus. Glutathione is considered to be the most
powerful, versatile, and important antioxidant in the body.
Glutathione is synthesized in the body from three amino
acids: Cysteine, glutamine and glycine. Cysteine is one of
the sulfur containing amino acids used for the synthesis of
glutathione (this amino acid is very critical in detoxification).
When an electron of the GSH is lost then it becomes
oxidized. When the level of oxidized form of this molecule is
increased then they linked with each other by a disulfide
bridge to form glutathione disulfide or oxidized glutathione
(GSSG).
The main protective roles of glutathione against oxidative
stress are: [i] glutathione is a cofactor for other detoxifying
enzymes like glutathione peroxidase (GPx), and glutathione
transferase [ii] GSH participates in amino acid transport
through the plasma membrane; [iii] GSH scavenges hydroxyl
radicals and singlet oxygen directly, detoxifying hydrogen
peroxide and lipid peroxides by the catalytic action of
glutathione peroxidase; [iv] Glutathione is able to reduce
oxidized Vitamin C and Vitamin E back to their unoxidized
state. Moreover, GSH in the nucleus involves in mechanisms
that are necessary for DNA repair and expression [18].
FREE RADICAL PRODUCTION DURING
INFLAMMATION
The interaction of the cellular immune system with
endogenous and/or exogenous antigens results generation of
ROS and RNS, leading to signaling cascades that trigger the
production of proinflammatory cytokines and chemokines
[19]. Inflammation is the primary immune system reaction to
Chronic Inflammation & Cancer Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 75
eliminate pathogens or other stimuli in order to restore the
cells to normal state or replace destroyed tissue with scar
[20]. After activation, innate immune system cells secrete
proinflammatory cytokines and chemokines that induce
ROS/RNS production [21]. In the innate immune system,
macrophages play a pivotal role in eliminating the pathogen
through the generation of reactive oxygen species including
superoxide, nitric oxide, hydrogen peroxide, hydroxyl
radical, peroxynitrite and hydrochlorous acid (Hocl) [22].
Inflammation reaction continues until the pathogens are
eliminated and the tissue repair process be completed [23].
Continued active inflammation response can lead to cell
damage or cellular hyperplasia following ROS overpro-
duction from inflammatory cells. During inflammation ROS
can interact with DNA in mitotic cells resulting in permanent
genomic mutation such as point mutations, gene deletions, or
gene rearrangement [24]. During inflammation cellular
antioxidant systems respond to free radical overproduction
by activating genes involved in DNA repair [25]. In chronic
inflammation the rate of ROS induced DNA damage is
extensive because this condition leads to depletion of cellular
antioxidants. Chronic inflammation predisposes cells for
transformation due to induction of recurrent DNA damage
by inflammatory cells, hence higher frequency of mutation
[26]. In addition, chronic inflammation induces increase of
growth factor production and growth-supporting stimuli.
Over all, it seems that chronic inflammations facilitates
cellular malignancy and transformation [27]. Based on these
facts, inflammation is considered to be a major precursor for
cancer development. To further elucidate the relationship
between chronic inflammation and ROS content in tissues,
we will review the role of inflammatory cytokines in
production of free radicals.
Cytokines are soluble mediators of intracellular commu-
nications. They contribute to a chemical signaling language
that regulates development, tissue repair, haemopoiesis,
inflammation, and the specific and non-specific immune
responses. Binding of cytokines to their receptors initiates
transmission of extracellular information into the cytoplasm
and the nucleus [28]. Cytokine receptors are usually directly
linked to the ion channels or G proteins. The information is
transmitted by various signaling pathways like nuclear factor
B and mitogen-activated protein kinase (MAPK) [29]. It
has been recognized that a variety of cytokines induces ROS
production in nonphagocytic cells by binding to their
specific receptors. Some of the well-known activated growth
factor receptors that induce ROS include: epidermal growth
factor (EGF) receptor, platelet-derived growth factor (PDGF)
receptor and vascular endothelial growth factor (VEGF)
receptor [30]. Inflammatory cytokines such as IL-1, IL-6,
TNF-, and IFN- have been shown to generate ROS in
nonphagocytic cells too [31]. The ROS produced by cytokine
induction can be an important signal for other biological
effects in cells such as proliferation and programmed cell
death [23]. For instance, TNF- enhances ROS production
by neutrophils, while IL-1-, TNF-, and IFN- stimulate the
expression of inducible nitric oxide synthase (iNOS) in
inflammatory and epithelial cells [32]. In animal models of
multiple myeloma, plasma cells require IL-6 for growth,
which is provided by macrophages in the chronically-
inflamed tissue [33]. IL-6 is stimulated by PGE2 derived
from cyclooxygenase-2 (COX-2), which is elevated in
inflammatory macrophages. This process can be inhibited by
anti-inflammatory drugs [34, 35]. TNF- is another
important inflammatory cytokine that is secreted mainly
from activated macrophages and induces ROS production in
many types of cells. TNF- Knockout mice show significant
decrease of skin tumor development in response to DMBA
[36]. IL-8 is an inflammatory chemokine, derived from
monocytes, macrophages, and endothelial cells, that has
important role in tumor angiogenesis. In addition, its role in
many types of tumors including: colon, bladder, lung, and
stomach cancer has been described [37].
CHRONIC INFLAMMATION AND CARCINO-
GENESIS
Many studies have demonstrated the direct relationship
between chronic inflammation and cancer [32]. It has been
estimated that chronic infection and the associated
inflammation contribute to approximately one-quarter of all
cancer cases worldwide [38-40].
A wide variety of chronic inflammatory conditions
predispose susceptible cells to neoplastic transformation
[41]. Inflammation is a multistep process that includes
injury, repair, and resolution. Inflammation process exerts its
effects on other cells through messenger molecules such as
cytokines, prostaglandins, chemokines and angiogenic
factors [42]. ROS/RNS and inflammatory cytokines, like
TNF- activate a transcription factor called nuclear factor
kappa-B (NFB) by phosphorylation and subsequent
proteasomal degradation. After that, NFB migrate to
nucleus and activates specific gene transcription [23]. NFB
induces the expression of genes involved in cell proli-
feration, apoptosis and carcinogenesis [43]. NFB can also
induce production of proinflammatory cytokines, which will
enhance the inflammatory responses. In normal state NFB
is inhibited by its inhibitory protein (IB) which can down
regulate the inflammatory response.
The main chemical effectors in inflammatory response
are free radical species derived from oxygen. Free radicals
may act as direct or indirect damaging agents through their
reaction with other chemical or structural components in
target cells. ROS can also recruit other inflammatory cells
leading to additional ROS production and amplify the
damage [32].
INFLAMMATION AND ANGIOGENESIS
Chronic inflammation is also associated with
angiogenesis [44]. Macrophages, platelets, fibroblasts, and
tumor cells are a major source of angiogenic factors such as:
basic fibroblast growth factor, vascular endothelial growth
factor, prostaglandins-E1 and E2 [37]. These inflammatory
angiogenic mediators augment the production of ROS/RNS
and subsequently, increase the risk of cancer [45]. Pros-
taglandins are derived from the metabolism of arachidonic
acid in inflammatory cells, and have been shown to
contribute to cancer development by many researches [46,
47]. It has been suggested that Prostaglandins can increase
the risk of cancer by inducing the expression of inflam-
matory cytokines, which in turn enhance ROS and RNS
production.
76 Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 Khansari et al.
Cyclooxygenase (COX) is a key enzyme responsible for
the biosynthesis of prostaglandins from arachidonic acid.
COX exists in two isoforms commonly referred to as COX-1
and COX-2. During inflammation COX-2 is the main
enzyme that is unregulated in the macrophages. This enzyme
is also expressed in noninflammatory cells such as fibro-
blasts, epithelial and endothelial cells. Bacterial infections
and inflammatory cytokines increase COX-2 expression [48,
49]. Many research and investigations revealed that COX-2
production is increased in many cancers such as colon,
breast, lung, esophagus, and head and neck cancer. Studies
from COX-2 transgenic mice and knockout mice confirm
that COX-2 plays a role in colon cancer development, both
through angiogenesis and through the activation of different
oncogenes, including v-src, v-ha-ras, her-2/neu and wnt [50].
Free radicals react with membrane phospholipids gene-
rating hydroperoxides, lipoperoxides and toxic aldehydes
such as MDA, which in turn may alter membrane
permeability and microcirculation.
It is now known that many oncogenes act by inhibiting
apoptosis, thereby conferring a survival advantage to
preneoplastic and malignant cells. On the other hand, several
chemotherapeutic drugs exert their action by promoting cell
death via increasing ROS production [51]. Carcinogenesis
may be mediated by ROS and RNS directly by chronic
inflammation (oxidation, nitration of nuclear DNA/RNA or
lipids), or may be mediated indirectly by the products of
ROS/RNS, proteins, lipids, and carbohydrates that are
capable of forming DNA adducts [52]. ROS can also
increase the expression of transcriptional factors such as c-
fos and c-jun involved in neoplastic transformation and
enhancement of tumor angiogenesis [32].
DIRECT EFFECT OF FREE RADICALS ON DNA
DAMAGE AND CARCINOGENESIS
To date, more than 100 oxidized DNA products have
been identified. ROS-induced DNA damage involves single
or double stranded DNA breaks; purine, pyrimidine or
deoxyribose modifications; DNA intrastrand adducts; and
DNA-protein crosslinks [53]. DNA damage can result in
either transcriptional arrest or induction/replication errors, or
genomic instability, which all these processes are associated
with carcinogenesis [54].
The importance of OH in DNA damage process is not
completely understood because it has a very short half-life
and must be produced directly adjacent to DNA to induce
damage. However, peroxynitrite (ONOO-) can diffuse within
cells, and cause damage during chronic inflammation [55].
The less reactive molecules such as nitric oxide (NO) can be
released from innate immune cells specially macrophages
and act on neighboring cells, leading to somatic mutations
and cancer [56]. Nitric oxide can react with superoxide and
form ONOO-. This reactive intermediate can induces
oxidative DNA damage. Moreover, ONOO- participates to
the formation of 8-oxo-7, 8-dihydro-20-deoxyguanosine and
8-nitroguanine, which are biomarkers for inflammation-
induced carcinogenesis [57-59]. It has been recognized that
8-nitroguanosine is a highly mutagenic molecule and can
give rise to G>T transversions [60,61]. In lung and liver
cancer, G>T transversions have been observed in vivo in the
ras gene and the p53 tumor suppressor gene [62]. These
findings indicate that ROS and RNS may participate in
carcinogenesis, by both activation of proto-oncogenes and
inactivation of tumor suppressor genes.
Oxidative damage to mitochondria is also implicated in
carcinogenesis. Hydrogen peroxide and other ROS activate
nuclear genes that regulate the biogenesis, transcription and
replication of the mitochondrial genome. Recently, a large
amount of evidence supports mitochondria involvement in
carcinogenesis [5]. MtDNA fragments have been found
inserted into nuclear DNA, suggesting a possible mechanism
of oncogene activation. As noted previously, MtDNA is
vulnerable to free radical damage because of the lack of
histone proteins [63-65]. Free radical induced MtDNA
damage reflects as mitochondrial respiratory chain dysfunc-
tion, which in turn increases the production of hydroxyl
radicals and further DNA damage [66, 67]. Mutations and
altered expression in mitochondrial genes encoding for
complexes III, IV, V, and I and in the hypervariable regions
of mitochondrial DNA have been identified in various
human cancers [68-70].
Free radicals can alter cell growth and tumor promotion
by activating signaling pathways, which result in the
induction of growth stimulatory proto oncogenes, like c-fos,
c-jun, and c-myc [71]. It has been shown that that phos-
phorylation and poly-ADP-ribosylation of chromosomal
proteins are involved in the transcription of c-fos by
oxidants, and that a pro-oxidant state can promote neoplastic
growth [72, 73]. Cancer promotion can be explained by a
consequence of extensive and continued free-radical related
damage [74].
Many investigations have shown that DNA is not the
only molecule at risk of oxidative damage. In addition to
DNA damage, free radicals interfere with cellular mutation
repair systems in parallel. These interference include:
function of proteins such as DNA repair enzymes, apoptotic
modulators, and the p53 protein which may be modified
during exposure to free radicals. It has been shown that p53
is post-translationally modified at crucial residues after
exposure to NO and its derivatives [75]. Moreover, DNA-
repair and signal-transduction molecules such as DNA-
protein kinases are activated by exposure to NO [75]. NO
can participate in carcinogenesis by influencing the proteins
that are crucial to cell function, including cell-cycle
checkpoints, apoptosis and DNA repair [76].
FREE RADICALS IN AGING
Generally, there are two types of theories describing the
aging processes: damage-accumulation theories [77] and
genetic theories [78]. Damage accumulation theories include
the “free radical theory”, the “glycation theory”, the “error
catastrophe theory”, the “membrane theory”, the “entropy
theory” and others, among which the “free radical theory” is
probably the most complex approach to explain the aging
processes. The “free radical theory” is based on the fact that
the random deleterious effects of free radicals produced
during O2 metabolism accumulate over time, causing
damage to DNA, lipids, and proteins [79]. The genesis of
aging starts with oxygen, occupying the final position in the
electron transport chain [6]. Even under ideal conditions,
Chronic Inflammation & Cancer Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 77
some electrons leak from the electron transport chain. These
leaking electrons interact with oxygen to produce superoxide
radicals. Under physiological conditions about 3% of the
oxygen molecules in the mitochondria are converted into
superoxide. As noted above, the primary site of radical
oxygen damage from superoxide radicals is mtDNA.
Therefore, extensive MtDNA damage accumulates over time
and eventually shuts down mitochondria, causing cells to die
and the organism to age. Many correlations between oxygen
consumption and aging have been observed [80]. Lowered
oxygen consumption explains why queen bees live 50 times
longer than actively flying worker bees, and houseflies that
are prevented from flying (by removing their wings) lived
much longer than flying insects. Larger animals consume
less oxygen per unit of body mass than smaller ones, and live
longer. Different rates of ROS generation also influence the
life span of animals. For example, rats and pigeons have
similar metabolic rates but different life spans (rat: 3 years,
pigeon: 30 years). in vitro Experiments show that pigeon
tissues generate ROS more slowly than rat mitochondria.
Caloric restriction in rodents plays an important role in the
aging process and is associated with increased DNA repair
capacity, decreased production of superoxide, and decreased
levels of DNA, lipids, and proteins damage. Longer-lived
species have more efficient antioxidant protective mecha-
nisms (SOD, carotenoids, GSH, glutathione peroxidase, and
Vitamin E) in relation to oxygen uptake rates than do the
short-lived species. Koya disclosed methods of treating a
proliferative disease, such as cancer, with bis (thio-hydrazide
amides) or a tautomer, pharmaceutically acceptable salt,
solvate, clathrate, or prodrug thereof, in combination with
hyperthermia treatment. Also disclosed are methods of
treating a proliferative disease, such as cancer, with bis (thio-
hydrazide amides) or a tautomer, pharmaceutically accep-
table salt, solvate, clathrate, or prodrug thereof, in combi-
nation with radiotherapy [81].
In humans, the level of oxidative DNA damage as
measured by urinary biomarkers can be modulated by caloric
restriction and dietary composition [82]. Consequently,
longevity may depend not only on the basal metabolic rate
but also on dietary caloric intake. The accumulation of free
radical-induced damage to biomolecules is illustrated by an
age-related increase in the serum 8-hydroxydeoxyguanosine
(8-OH-dG) level in disease-free individuals over a range of
15-91 years [5]. Several studies have reported the in vivo and
in vitro accumulation of 8-OH-dG as well as other lesions
with advancing age, both in nuclear and mitochondrial DNA
[83]. DNA repair capacity correlates with species-specific
life span, and this repair activity appears to decline with
advancing age. However, several animal studies reported that
age-related increase in 8-OH-dG in nuclear and
mitochondrial DNA is due to a tissue’s increased sensitivity
to oxidative damage rather than age-related decreased repair
capacity. However, antioxidant level does not change
significantly with advancing age. Human studies have shown
that the level of SOD, GSH, catalase, and ceruloplasmin
were not altered among a wide-range of age groups [84].
Studies in many different animals show that aging is
frequently associated with the accumulation of oxidized
proteins. The role of protein modification in aging is
illustrated by different enzymes isolated from younger
animals that are catalytically more active and more heat
stable than the same enzymes isolated from older animals
[85]. Enzymes derived from young animals exposed to
metal-catalyzed oxidation led to changes in activity and heat
stability similar to those observed during aging. Thus, it was
proposed that ROS-mediated protein damage is involved in
the aging processes.
AGE-ASSOCIATED CHANGES IN LIPID
OXIDATION
A number of studies have examined the effects of aging
on lipid peroxidation in mammalian tissues by measuring
thiobarbituric acid-reactive (TBARS) content as a marker of
endogenous lipid peroxidation [86]. It has been reported that
aging is associated with a 50% increase in TBARS in male
rat’s liver, but the effect of aging in female rats was a 50%
decrease in hepatic TBARS. Curiously, the age-dependent
differences in TBARS concentration were not related to
changes in antioxidant molecules [87]. It has been reported
that, age-associated changes are observed in some organs but
are not evident in others. The data for male Wistar rats, for
instance, indicate that TBARS may increase with age in liver
and brain, but not in heart or lung [88]. Myhill et al.
Disclosed a method for reducing the undesirable side effects
of free radicals in a subject by administering to a subject in
need of such antioxidants an effective amount of antioxidant-
promoting composition of the invention [89].
Although fewer similar studies have been carried out in
mice, these studies also have produced conflicting results.
For example, hepatic TBARS concentrations were elevated
in old female C57BL mice but were unaffected by aging in
males [90,91]. The effects of age and gender differ from
those reported for rat liver, where elevated TBARS are
observed in old males, but not in old females [86].
Altogether, the findings suggest that age-associated changes
are species-, strain-, sex-, and tissue-specific, and that
increased lipid peroxidation is not an inevitable consequence
of aging in any organ.
AGE-ASSOCIATED CHANGES IN ANTIOXIDANT
Review of the published data indicates that age-related
changes in antioxidant defenses are quite varied. Many
studies have shown that one or more antioxidant enzymes or
molecules decrease as a consequence of aging. This has led
to the belief that aging is associated with a decrease in
antioxidant status and that age-dependent increases in lipid
peroxidation are consequences of diminished antioxidant
protection [86].
Changes in mitochondrial enzymes differ from those
found in cytosolic enzymes. Significant differences between
young adult and old rats were demonstrated for GSH
peroxidase, superoxide dismutase, and GSSG reductase
activities. These differences included age-related increases as
well as decreases and were different for males than for
females [88]. Heaney et al. utilized fructose and other
monosaccharides for the treatment of cancer. They used
these compounds to mimic or corrupt metabolic pathways of
fructose and/or signal transduction pathways related to
cancer cells for the treatment of cancer [92].
78 Recent Patents on Inflammation & Allergy Drug Discovery 2009, Vol. 3, No. 1 Khansari et al.
CURRENT & FUTURE DEVELOPMENTS
In one half century ago, Harman proposed free radical
theory of aging based on his observation that irradiation of
living things will increase free radicals in the body inducing
changes similar to aging processes and shortening their
lifespan [91].
A free radical is any chemical species like: molecule, ion
or atom that contains an unpaired or odd electron in its outer
orbit of its molecule. Most common source of these
chemicals in biological system is oxygen and to a lesser
extends nitrogen molecules. The most abundant source of
free radical formation is mitochondria which use more than
90% of oxygen intake to burn proteins, lipids, and
hydrocarbons and convert them to energy and water (cellular
metabolism and energy production). This is the link between
the high calory theory of aging and free radical theory of
aging. The second source of free radicals is the byproducts of
oxidative burst in activated neutrophils and monocyte/
macrophages in response to inflammation and microbial
infections or even tissue injuries leading to release of pro-
inflammatory cytokines. This is the basis of “inflammation
theory of aging”.
In addition to generation of free radicals, as byproducts
of cellular metabolism and immune response to infection,
intracellular induction of this molecule from environmental
sources such as ultraviolet and ionizing radiation, ozone, etc.
contribute to consumption of free radical scavenging
mechanism (antioxidants) resulting to excessive level of free
radical in the body and leading to oxidative stress.
Many important molecules including proteins, lipids, and
nucleic acid chains are very susceptible to oxidizing
reactions; thus, it is not unexpected to see many deteriorating
events following oxidative stress leading to decrease
longevity of the cells as well as living organisms. In fact,
certain strains of fruit flays that have greater resistance to
oxidative stress, exhibit longer lifespan. Free radical attacks
to macromolecule especially highly susceptible molecules
such as DNA and RNA can knock out bases or cause a
strand breakage with potential to cellular transformation or
even cell apoptosis. It has been estimated more than 10000
oxidative hits to DNA occur in an average human cell per
day [3]. This would describe how oxidative stress can
increase rate of cell transformation (malignancy).
It has been shown that nonsteroidal anti-inflammatory
drugs (NSAID) can prevent incidence of several cancers in
families with history of high cancer risk. It has also been
shown that indomethacine blocks carcinogenesis by reducing
the production certain cytokines called pro-inflammatory
cytokines (IL-1, IL-6, IL-15 and TNF-). Moreover, it has
been demonstrated that those people who regularly take
NSAID show a lower cancer risk [93].
On the basis of these considerations, pro-inflammatory
cytokines are key elements in malignant transformation of
the cells and pro-angiogenic activities leading to cancer;
thus, chronic inflammation should be considered as a high
risk factor for cancer causing especially in elderly people;
since, increase of oxidizing reaction in one hand and immune
senescence in the other hand will predispose the individual to
harbor tumor and die from it. Based on these analogies, it
should be recommended that elderly people should consume
higher anti-oxidant compounds, and take NSAID regularly.
It is also recommended that any chronic inflammatory
disease and /or infection must be taken seriously and treated
effectively as soon as possible by the practitioners.
ACKNOWLEDGEMENT
The authors would like to thank the Department of
Immunology, School of Medicine, TUMS for providing
partial financial support for this article.
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... This specific condition can lead to cellular damage affecting intracellular structures, including protein, lipids, and DNA, as well as mitochondrial function, extra-cellular matrix remodelling, and cell growth [9]. The exposure to chronic OS induces a subclinical state of increasing cell damage that builds up over time, facilitating tissue alteration/remodelling, selective system failures, and finally disease [7,9,11]. On the other hand, OS-induced damage to tissues can also trigger an IR and thus the release of inflammatory mediators, which in turn can directly induce OS [12,13]. ...
... In turn, the increased levels of pro-inflammatory cytokines result in the hepatic generation of acutephase proteins, including C-reactive protein (CRP). Its release and secretion further fuel the recruitment and accumulation of inflammatory cells to the damage site, accelerating the production of reactive species and, thereby, further stimulate ongoing OS [7,12,13]. Therefore, the vicious circle linking OS and IRs sustains and amplifies all stages of the disease. ...
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... ROS are generated endogenously, but there are also many exogenous sources including cigarette smoke, ultraviolet radiation, and metal-catalyzed reactions [3,4]. Infections, inflammatory processes, especially those that are chronic, ischemia, senescence, physical and psychological stress are the main factors involved in generating oxidative stress in the human body [5]. The accumulation of high amounts of ROS in the skin is associated with structural changes in cell components, the release of inflammatory cytokines, apoptosis, activation of transcription factors such as activator protein 1 (AP-1), mitogen-activated protein kinase (MAPK) and nuclear kappa factor B (NF-kB). ...
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