ANTIOXIDANTS INHIBITORS

FOR
CANCER THERAPY
 INTRODUCTION
Cellular oxidants
Gene expression (ROS,RNS, FREE RADICALS)
Endogenous
antioxidants

Cell ,organelles & Biomolecules

Dysfunction
Dietary
antioxidants

Disease
 ANTIOXIDANTS

An antioxidant is anything which can prevent or inhibit oxidation

A good antioxidant should

 Specifically quench free radicals
 Chelate redox metals
 Interact with other antioxidants within the antioxidant network
 Have a positive effect on gene expression
 Be readily absorbed
 Have a concentration in tissues and biofluids at a physiologically
relevant level.
 Work in both aqueous and/or membrane domains.
MAJOR ANTIOXIDANTS IN BIOLOGICAL
SYSTEM
Enzymatic antioxidants

 Superoxide dismutase
 Catalase
 Glutathione peroxidase

Non Enzymatic antioxidants

 Vitamin C
 Vitamin E
 Glutathione
 Superoxide dismutase (SOD)
First characterized antioxidant enzymes
Most effective intracellular enzymatic antioxidant
Catalyse the dismutation of superoxide anion to molecular oxygen
and to less reactive species H2O2.

O2.- + O2.- +2H+ H2O2 + O2

There are three forms of SOD

1.Cytosolic superoxide dismutase (Cu,Zn-SOD)
2.Mitochondrial superoxide dismutase (Mn-SOD)
3. Extracellular superoxide dismutase (ECSOD)
 SOD IN CARCINOGENESIS
H2O2
Oxidative stress
Ap1 and nfkb
Activation
Cellular response

Activation of
SOD
MMPS

Superoxide content
Cellular remodelling
and
tumor invasion
Reduces ROS mediated cellular growth
 CATALASE
 Tetrameric antioxidant enzyme
 Molecular weight 240 kDa
 Located in a cell organelle called peroxisome
 This heme enzyme is responsible for detoxification
of various phenols alcohols and hydrogen peroxide
 Promoted the conversion of hydrogen peroxide
to water and molecular oxygen

2H2O2 2H2O + O2

 One molecule of catalase can convert approx. 6 million molecules

of H2O2 to H2O and O2 per minute
 Catalase activity was found to be increased in CRC
 GLUTATHIONE PEROXIDASE
Glutathione peroxidase are another group of enzymes
capable of reducing hydroperoxides, including lipid hydroperoxides
using glutathione as substrate.

There are two types of the enzymes GPx

1. Selenium dependent GPx.
2. Selenium independent GST

2GSH+ H2O2 GSSG + 2H2O

2GSH +ROOH GSSG + ROH + 2H2O

 GLUTATHIONE PEROXIDASE FAMILY
Plasma GPx
* EC antioxidant
* oxidative host defense

Cytosolic GPx
Phospholipid hydroperoxideGPx
* IC antioxidant
GPx *IC antioxidant
*Regulation of
famil *Regulation of
gene expression
y gene expression
*Sperm maturation

Sperm nuclei GPx Gastrointestinal GPx

*Chromatin condensation *intestinal peroxide barrier
*antioxidative DNA protection *Xenobiotic metabolism
GLUTATHIONE PEROXIDASE IN
CARCINOGENESIS
Tumour cells

Increased H2O2 generation

Increased GPx activity

Increased GSSG formation

Reduced GSH concentration

CATALYTIC CYCLE OF GLUTATHIONE
PEROXIDASE

GPx - SeOH
-
GPx Se
GSH
GSSG + H+
H O
GSH 2
GPx- Se - GSSG
 Vitamin C

Water soluble antioxidant and works in aqueous environments of

the body.

Major antioxidant in human plasma.

Reduces alpha tocopherol as well as peroxides and ROS

such as superoxide

Mainly prevent lipid hydroperoxide formation in plasma lipoproteins.

Primary antioxidant partners are vitamin E and carotenoids.

 Vitamin E
Fat soluble vitamin
Present in biological membranes
Majors membrane bound antioxidant employed by the cell
Its main antioxidant function is protection against
lipid peroxidation
NAD+

. . DHLA+
LOO T-OH ASc

LOOH . ALA
T- O ASCH-

NADH+
+
+H
Vitamin E in carcinogenesis
Vitamin E 200 IU/day

Induce p21 wafi/cip1

(powerful cell cycle inhibitor)

Trigger apoptosis of cancer cells

Reduced incidence of CRC

 GLUTATHIONE

Major thiol antioxidant.

Highly abundant in the cytosol nuclei mitochondria.

GSH + R. GS.+ RH

.
GS.+GS GSSG

GSH Anticancer drug induced apoptosis

Drug resistance
ANTIOXIDANTS SUPPRESS CANCER FORMATION
GR

Cu SOD GSH GSSG

Mn SOD
Inflammation GPx
EC SOD
Chemicals
O2- H2O2 H2O + O2
Endogenous sources
Radiation
.
OH+.OH Catalase

Protoncogene activation
Tumour suppressor inactivation
Incomplete DNA repair
Angiogenesis stimulation
CANCER
Lipid peroxidation
ANTIOXIDANTS PROMOTES CANCER GROWTH
Genetic alterations
Normal cells Transformed cells

Express high levels of

Antioxidants.

Redox mediated
Scavenge free radicals immuno, radio
chemo therapy
Lack of action of therapeutic agent
due to decreased ROS

Cancer
Tumour cell’s antioxidant mediated potential
self defense mechanism
EXPERIMENTAL EVIDENCE FOR ANTIOXIDANT
MEDIATED DRUG RESISTANCE
Hirose et al.,1993
Cells lack/low expression
of MnSOD Sensitive to TNF mediated cytotoxicity

Nokano 1996
Cells constitutively produced Cytotoxicity
or cells engineered to express Resistance to
high MnSOD

Maeda et al 1993 Increased Redox mediated

Tumour cell lines expressing Resistance to Chemotherapeutic
high levels of MnSOD agents
ANTIOXIDANTS - TUMOUR SUPPRESSOR
OR TUMOUR PROMOTERS?
ROS

Involved in
Second messenger Highly toxic to
mutagenesis
For cytokines Established tumour
& carcinogenesis

Promotes Kills cancer cells

cancer growth

Opposing mechanism of actions

with a single target.(DNA)
ROS - ANTIOXIDANTS - CELL HOMOESTASIS

ROS Cell homeostasis ANTIOXIDANTS

Increased Decreased

In tumour Increase
Tisssues Susceptibility
To peroxidative
attack
Decrease ROS

DNA damage
Develop and disease
Utilised
chemoresistance
By tumour cells
For growth
 CONCLUSION
Normal cells
Antioxidant
supplementation
Initiation
Antioxidant
supplementation
Promotion

Progression

cancer