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REACTIVE OXYGEN SPECIES MANAGEMENT; A
STEP TO DEVELOP ANTI-CANCER THERAPY
Ms. Bushra Allah Rakha
Lecturer
Department of Wildlife Management
PMAS-AAUR
Reactive oxygen species (ROS) act as a second
messenger in cell signaling and are essential for
various biological processes in normal cells.
 Any aberrance in redox balance may relate to
human pathogenesis including cancers.
 Since ROS are usually increased in cancer cells
due to oncogene activation, relative lack of blood
supply or other variances and ROS do involve in
initiation, progression and metastasis of cancers,
ROS are considered oncogenic. The mechanism of
cancer initiation is shown in figure 1.

Exogenous source:
UV light
Ionizing Radiation
Inflammatory cytokines
Pathogens
Endogenous source:
Mitochondria
Peroxisomes
Cytochromes P450
Figure No: 1
ROS
Oxidative
stress
Damage to Nucleic acid, proteins and lipids
Chromosomal Instability Mutations
Loss of organelle function
Membrane damage
Cancer
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ROS, mainly consisting of superoxide anion radical,
singlet oxygen, hydrogen peroxide (H2O2) and the
highly reactive hydroxyl radical, as a group of
molecules harmful to cells, tissues and organisms.
However, ROS serve as a second messenger in cell
signaling and are essential for various biological
processes in normal cells.
Physiologically generated ROS are normally reduced
by non-enzymatic and enzymatic anti-oxidizing
agents, such as glutathione(GSH), thioredoxin (Trx),
superoxide dismutase (SOD), catalase and
peroxidases.
Cellular oxidative stress, an imbalance of redox state,
results from exposure to higher levels of ROS, which
are not detoxified by cellular antioxidative agents.
Therefore, as well known, ROS, when present in
a very high concentration, can damage cellular
proteins, lipids and DNA, giving rise to
senescent, degenerative or fatal lesions in cells,
which are related to many human diseases
including cancers, cardiovascular and neurodegenerative diseases.
 This DNA damage and division of cells with
unpaired or mispaired damage leads to
mutations.
 Mutations involve modification of guanine
causing G
T tranversions and p53 gene mutations.

Mutations of the p53 gene are found in more than
50% of malignancies and are the single most
common molecular abnormality in human cancer.
 Loss of p53 function is associated with loss of cellcycle control, decreased apoptosis, and genomic
instability.
 The p53 protein can be regulated by different posttranslational
modifications
such
as
phosphorylation of serine and/or threonine
residues,
acetylation,
ubiquitylation,
or
sumoylation of lysines residues.

ROS can function upstream of p53 and regulate
p53 activity and that ROS production can also be
a downstream effect of p53 activation.
 The redox status and consequently the function
of p53 can be affected by redox molecules such as
glutathione and thioredoxin/thioredoxin
reductase.
 For example, S-glutathionylation or oxidation of
p53 cysteine residues under oxidative stress was
associated with a loss of p53 protein function.

THE ROLE OF REACTIVE OXYGEN SPECIES
(ROS) IN CANCER CELL GROWTH AND
METASTASIS.
PARADOXICAL ROS-MANIPULATION
STRATEGIES IN CANCER TREATMENT
ROS molecules due to their chemical composition
are considered as harmful to cells, tissues and
organisms.
 ROS serve as a second messenger in cell
signaling and are essential for various biological
processes in normal cells.
 Physiologically generated ROS are normally
reduced by non-enzymatic and enzymatic antioxidizing agents, such as glutathione(GSH),
thioredoxin (Trx), superoxide dismutase (SOD),
catalase and peroxidases.

REASONS FOR ANTI-CANCER THERAPY
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ROS contribute to cancer initiation, promotion and
progression as well as maintenance of tumor cell
phenotypes.
Cancerous cells have increased ROS generation
Increased ROS is usually accompanied with oncogene
activation that is the initial steps of malignant
transformation
Although the causative relationship of ROS increase
and oncogene activation remains unclear, oxidative
DNA damage has long been thought to play a role in
carcinogenesis and malignant transformation.
However, oxidative DNA damage may be necessary,
but not sufficient, for cancer development.
ROS VS GENOMIC INSTABILITY
ROS act of
pyrimidines, purines,
chromatin proteins
Cause base
modification, DNA
adduction, gene
mutation
Point mutations
become
carcinogenic
ROS VS PROLIFERATION
Ligand
mediated
activation
Growth factor
receptor
supression by
PTP
ROS inhibit PTP
and growth related
ligase C-Cb1
Accumulation of ROS cause degradation
of MAPK phosphatase 3 that cause
tumorigenicity
ROS VS ANGIOGENESIS

ROS
Cause neo-vascularization
Increased
vasularization
leads to rapid
tumor expansion
Neo-vascularization is due
to presence to H2O2 in
ROS, which increase
expression of Vascular
Endothelial Growth Factor
(VEGF), receptor and
MMP activity
ROS VS METASTASIS
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Exogenously administration of ROS would enhance
certain stages of metastatisis, while anti-oxidant
treatment could attenuate metastatic progress.
Even surgical procedures, a primary option for
treating tumors, can lead to the increased growth of
metastatic tumors by ROS generation.
Possible mechanisms involve aberrant expression of
integrins and MMPs and suppression of anoikis.
Intriguingly, causative relationship between ROS
and tumor metastasis is due to replacement with
mitochondria DNA (mtDNA) derived from a highly
metastatic mouse tumor cell line, an originally poorly
metastatic cell line acquires the metastatic potential.
The transferred mtDNA contain mutations producing
a deficiency in respiratory complex I activity and are
associated with overproduction of ROS.
ROS VS. ESCAPING FROM IMMUNO-ATTACK
The intratumoral lymphocytes in many human
malignant tumors are responsible for attacking
tumor cells.
 However, they could be inhibited by ROS derived
from NADPH oxidase in adjacent
monocytes/macrophages (MO).
 In vitro data suggest that immunotherapeutic
cytokines such as interleukin-2 (IL-2) or
interferon-α (IFNα) only weakly activate T cells
or natural killer (NK) cells in a reconstituted
environment of oxidative stress.
ANTI-OXIDANT CANCER THERAPIES
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To intake dietary or supplementary antioxidants

To enhance ROS scavenging enzymes
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To target NADPH oxidase
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To manipulate nitroxide compounds
PRO-OXIDANT CANCER THERAPY
ROS are responsible for triggering cell death and
reversing chemo-resistance in tumors
 ROS-inducing tumors with antioxidants is
reasonable, ironically, the mechanism underlying
that many chemotherapeutic agents and ionizing
radiation exert on tumor cell kill is not associated
with the increase of antioxidants, but rather the
production of more ROS leading to irreversible
oxidative stress.
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ROS VS. APOPTOSIS
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Both death receptor- and mitochondriamediated
apoptosis depend a lot on ROS.
Fas
ligand
NADPH
oxidase
Required for
yes/EGFR/FAS
interactions of Fastyrosine
phosphorylation
Triggers
ROS
formation
Involve a siphingomylinase
and Pkczeta-dependant
phosphorylation pf p47 phox
Cause Fas-associated death domain, caspase8
and apoptosis
Mitochondria-mediated apoptosis is haracterized
by an opening of permeability transition (PT)
pore complex which results in cytochrome c
release, apoptosome formation and culminate
caspases activation.
 ROS are known to impact the stability of PT pore
complex both through cell signaling cascade and
through oxidative modification of components of
PT pore complex.
 This occurs through the following mechanism

To induce the dimerization and activation of
ASK1
 To release MEKKI from binding with inhibitory
molecules such TRX, GST
 To inhibit activity of protein tyrosine
phosphotase to relieve the activity of SRC to
initiate downstream cascade
 This activate the ROS, JNK would translocate to
close mitochonrial membrane to activate
destabilizing proteins leading to opening of PT
pore complex.
 This complex affcets both the inner and outer
mitochonrial membranes.
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ROS VS NECROSIS
Necrotic cell death invole ROS accumulations
 This accumulation is due to RIP, TRAF2 and
FADD
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ROS VS AUTOPHAGIC CELL DEATH
Autophagy play important role in cellular
response to oxidative stress.
 The outcome of autophagy results in removal of
pathogens, damaged organelles and proteins to
programmed cell death.
 ROS is used recently in killing cancer cells
through autophagy.
 The effectiveness and selectivenss are indicated
for a few type of cancer cells that are resistant to
proapoptotic therapies, such as radiotherapy and
chemotherapy
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ROS VS CHEMO-SENSITVITY
PRO-OXIDANT CANCER THERAPIES
1.
Generation of ROS directly in tumour cells
INHIBTING THE ANTIOXIDATIVE ENZYME
SYSTEM OF TUMOUR CELLS.
CAUTION IN DECETION OF ROS: OXIDATIVE
OR REDUCTIVE
To establish the role of ROS in cancer treatment
involves to measure them correctly.
 Due to difference in methodology, some agents
called as oxidants and some anti-oxidants.
 Delayed measurement also results in opposite
conclusion about the redox role of the agent.
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CONLUSIONS
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Targeting cancer cells is currently not only an idea but also start to go
to patient beds.
Both oxidant and anti-oxidant elevated levels are shown to be
effective in cancer treatment.
Selectivity between tumor and nontumor cells may depend on
difference of their redox status.
However, a combinational set of parameters including redox status,
antioxidant enzymes expression, cell signaling and transcription
factor activation profiles, namely “redox signaling signature” in a
given type of cancer cells, is waiting for being developed.
And then it can be used as an indicative for choosing ROS-elevating
or ROS-depleting therapy specific to certain type of cancer cells.
Further research also needs to explain in respect of molecular
mechanism why each strategy exerts different effects on cancer and
normal cells. In clinical setting individualized choice of an optimal
ROS-manipulation therapy may require more accurate and
convenient measurements for ROS as well as an integrative “redox
signaling signature” for prediction of efficacy and systemic toxicity.
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