REACTIVE OXYGEN SPECIES MANAGEMENT; A STEP TO DEVELOP ANTI-CANCER THERAPY Ms. Bushra Allah Rakha...
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Transcript of REACTIVE OXYGEN SPECIES MANAGEMENT; A STEP TO DEVELOP ANTI-CANCER THERAPY Ms. Bushra Allah Rakha...
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.
Endogenous source:MitochondriaPeroxisomes
Cytochromes P450
Exogenous source: UV light
Ionizing RadiationInflammatory cytokines
Pathogens
ROS
Oxidative stress
Damage to Nucleic acid, proteins and lipids
Chromosomal Instability MutationsLoss of organelle function
Membrane damage
Cancer
Figure No: 1
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 neuro-degenerative 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 cell-cycle control, decreased apoptosis, and genomic instability.
The p53 protein can be regulated by different post-translational 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 anti-oxidizing agents, such as glutathione(GSH), thioredoxin (Trx), superoxide dismutase (SOD), catalase and peroxidases.
REASONS FOR ANTI-CANCER THERAPY
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 PROLIFERATIONLigand
mediated activatio
n
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
Neo-vascularization is due to presence to H2O2 in ROS, which increase expression of Vascular Endothelial Growth Factor (VEGF), receptor and MMP activity
Increased vasularization leads to rapid tumor expansion
ROS VS METASTASIS 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
To intake dietary or supplementary antioxidants
To enhance ROS scavenging enzymes
To target NADPH oxidase
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.
ROS VS. APOPTOSIS
Both death receptor- and mitochondriamediated apoptosis depend a lot on ROS.
Fas ligand
NADPH oxidase
Triggers ROS
formation
Involve a siphingomylinase and Pkczeta-dependant
phosphorylation pf p47 phox
Required for yes/EGFR/FAS
interactions of Fas-tyrosine
phosphorylation
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.
ROS VS NECROSIS
Necrotic cell death invole ROS accumulations This accumulation is due to RIP, TRAF2 and
FADD
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
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.
CONLUSIONS 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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