Transcript Slide 1 - Home - KSU Faculty Member websites

PHL 472
Chemical Carcinogens
Abdelkader Ashour, Ph.D.
4th Lecture
Classification of Carcinogens According to
the Mode of Action, Based on Reactivity with DNA
II. Epigenetic (non-genotoxic) Carcinogens
 No direct chemical reactivity with DNA
 They are non-mutagenic
 Usually act as tumor promoters
 There are no common chemical structural features between these
chemicals
 Their carcinogenic potential is generally lower than that of
genotoxic carcinogens
Epigenetic Carcinogens, Mechanisms
1.
Prolonged stimulation of cell proliferation, via chronic cytotoxicity or increased
secretion trophic hormones
2.
Inhibition of apoptosis in cells with DNA damage
3.
Impairment of DNA-replication fidelity and DNA-repairing machinery
4.
Dysregulated gene expression

Altered DNA methylation status in the genes that control cell growth and
differentiation
5.
Induction of metabolizing enzymes
6.
Dysregulated cell signaling via receptor- or non-receptor-mediated pathways
7.
Persistent immunosuppression, leading to compromised immunosurveillance
8.
Oxidative Stress

Indirect DNA damage

Induction of cell proliferation signaling cascades
Epigenetic Carcinogens, Mechanisms
Cell Replication is Essential for Multistage
Carcinogenesis
 Decreases time available for DNA repair
 Converts repairable DNA damage into non-repairable mutations
 Necessary for chromosomal aberrations, insertions, deletions and gene
amplification
 Clonally expands existing cell populations
 Examples: Epidermal growth factor, hepatocyte growth factor, estrogens
Epigenetic Carcinogens, Mechanisms
Apoptosis
 Programmed Cell Death (Apoptosis): Active, orderly and cell-type-specific
death distinguishable from necrotic cell death (passive process):
 Induced in normal and cancer cells
 Non-random event
 Result of activation of a cascade of biochemical, gene expression and
morphological events
 Tissue and cell specific
 Growth factors and mitogens inhibit apoptosis
Epigenetic Carcinogens, Mechanisms
Alteration of Gene Expression
 Nuclear (hormone-like) receptors
 Kinase cascades
 Calcium-mediated signaling
 Transcription factors
 Gene methylation status (hypo  enhanced gene expression; hyper  gene
silencing)
 The next four slides are just for your own information
Intracellular Receptors
 These receptors could be cytosolic or nuclear
 Several biologic signals are sufficiently lipid-soluble to cross the plasma
membrane and act on intracellular receptors.
 Examples of such ligands include corticosteroids, mineralocorticoids, sex
steroids, vitamin D, and thyroid hormone. They can stimulate the transcription of
genes in the nucleus by
 binding to nuclear receptors
 This binding of hormone exposes a normally hidden domain of the receptor
protein, thereby permitting the latter to bind to a particular nucleotide sequence
on a gene and to regulate its transcription.
 End result is an alteration in gene transcription and therefore protein synthesis
 Actions: slow-acting (hours), long lasting
Nuclear Receptors, an example
 Mechanism of glucocorticoid
action.
 A heat-shock protein, hsp90,
binds to the glucocorticoid
receptor polypeptide in the
absence of hormone and
prevents folding into the active
conformation of the receptor.
 Binding of a hormone ligand
(steroid) causes dissociation of
the hsp90 stabilizer and permits
conversion of glucocorticoid
receptor to the active
configuration.
 The active glucocorticoid receptor
binds to a particular nucleotide
sequence on a gene  altered
transcription of certain genes
Kinase-linked Receptors,
Activation of Ras following binding of a
hormone (e.g., EGF) to an RTK.
1.
2.

The adapter protein GRB2 binds to a specific
phosphotyrosine on the activated RTK and to
Sos, which in turn interacts with the inactive
Ras·GDP.
The guanine nucleotide – exchange factor
(GEF) activity of Sos then promotes formation
of active Ras·GTP.
Note that Ras is tethered to the membrane by a
farnesyl anchor
Kinase-linked Receptors,
Kinase cascade that transmits signals
downstream from activated Ras protein
1.
Activated Ras binds to the N-terminal domain of
Raf, a serine/threonine kinase.
2.
Raf binds to and phosphorylates MEK, a dualspecificity protein kinase that phosphorylates
both tyrosine and serine residues.
3.
MEK phosphorylates and activates MAP
kinase, another serine/threonine kinase.
4.
MAP kinase phosphorylates many different
proteins, including nuclear transcription factors,
that mediate cellular responses.
Chemical
Carcinogens,
Representative
Members
Modifying Factors in Chemical Carcinogenesis
I.
Interaction with DNA
 A great body of information indicates that interaction with DNA is the critical
factor in chemical carcinogenesis.
 Several distinct sorts of data have been gathered. Relevant findings are as
follows:
1.
2.
3.
In general, carcinogens are mutagens, indicating that they have the potential to
interact with DNA.
Within groups of related carcinogenic chemicals, carcinogenic potency
correlates best with ability to interact with DNA.
Patients with DNA repair defects, such as xeroderma pigmentosum (defect in
repair of damage induced by UV and bulky aromatic chemicals), have increased
incidence of cancer.
Modifying Factors in Chemical Carcinogenesis
II. Environment:
The most impressive feature of cancer epidemiology is a high degree of geographic
variability in the incidence of specific forms of cancer. This can easily be seen if one
compares incidences between countries or between regions within a country
III. Genetic factors: They influence some specific cancers, this influence is a major
one. The sorts of genetic involvement which have been described are:
1. Single gene - probably directly involved in carcinogenesis. Example: retinoblastoma.
2. Single gene - predisposes to cancer. Example: xeroderma pigmentosum, a DNA repair
defect
3. Familial predisposition, probably polygenic. Example: increased incidence of breast
cancer in women whose mother or sister have had breast cancer
 Environment vs. Genetic factors :
 Some of the most productive studies that have been used were analyses of changes
in cancer incidence occurring when groups of people emigrate from one country to
another
 In such studies (next slide), genetic factors are essentially held constant, and effects
of environment can be observed
 In most cases, dramatic changes in cancer incidence are seen in the immigrant
populations, and such changes generally lead to a cancer incidence similar to that of
the natives in the immigrants' new homeland
Modifying Factors in Chemical Carcinogenesis
IV. Biological behaviors of the chemical carcinogen:
1. Site of action: Chemicals can act both locally and distally, e.g., benzo(a)pyrene
painting causes skin tumor, whereas DMBA painting causes tumors of the skin
and breast and also leukemia
2. Tissue responsiveness: There appears to be a great variation in tissue
responsiveness
 2-naphthylamine bladder tumor; urethane lung tumor; zinc testis tumor; tin
and nickel sarcoma, etc
3. Species specificity: 2-naphthylamine causes bladder cancer in man, dog and
hamster, but only liver cancer in mouse and no effect in rats.
4. Sex specificity: Hepatocarcinogens are more effective in male rats
 Female reproductive history: Late age at first pregnancy is associated with enhanced
risk of breast cancer, while zero or low parity is associated with increased risk of
ovarian cancer
5. Age: Many carcinogens are ineffective as transplacental carcinogens at
preimplantation but more effective after organogenesis begins, and more so at
postnatal life before immune system develops
Modifying Factors in Chemical Carcinogenesis
IV. Biological behaviors of the chemical carcinogen:
6. Diet: Diet greatly influences the effect of carcinogens e.g., caloric restriction in
general reduces cancer incidence (and vice versa). Phenylalanine- and
cysteine-deficient diets reduce breast cancer in mice. Azodye induced liver
tumors in rats are enhanced in the presence of vitamin B6 but decrease in the
presence of B2
 The most common mechanism of diet-associated carcinogenesis in humans is the
action of major dietary constituents (mainly fat and carbohydrate) as promoting
agents
7. Dose responsiveness. Carcinogen effect also appears to be dose dependent,
additive and irreversible. Large single dose or fractional doses appear to induce
the same incidence of tumors
8. Latency. Carcinogenesis requires time. The latent period could be shortened by
means of large doses, but a certain minimum period called the "absolute
minimum period of latency" is required
 The long latent period raises the question of whether factors other than true
carcinogens might act during the latent interval
 Both in vivo and in vitro results suggest that transient short exposure to carcinogen
causes irreversible changes, but this must be followed by several cell divisions
before neoplastic cells become detectable
Modifying factors in chemical carcinogenesis
V. Life style
 Unhealthy lifestyle habits such as: excess alcohol consumption; inhalation of
tobacco and related products; the ingestion of certain foods and their
contamination by mycotoxins (such as aflatoxin B1; a complete carcinogen);
are responsible for higher incidences of certain types of neoplasias in a
number of population groups
VI. Immune system
 Immune system may have a protective role in tumor development (i.e.,
preventing tumor formation)
 Small accumulations of tumor cells may develop and because of their possession
of new antigenic potentialities provoke an effective immunological reaction with
regression of the tumor
 Mice with induced immunodeficiencies showed a high susceptibility to virally
induced tumors and a greater tendency to develop spontaneous lymphomas
compared with immunocompetent mice
 At the same time, the immune system also may function to promote or select
tumor variants with reduced immunogenicity, thereby providing developing
tumors with a mechanism to escape immunologic detection and elimination.
 This is called: tumor-sculpting actions of the immune system on developing tumors
Modifying factors in chemical carcinogenesis
VII. Inflammation
 Inflammation caused by uncertain aetiology (e.g. ulcerative colitis,
pancreatitis, etc) is one the modifying factors in chemical carcinogenesis
 Inflammation orchestrates the microenvironment around tumours, contributing
to proliferation, survival and migration.
 Cancer cells use selectins, chemokines and their receptors for invasion,
migration and metastasis.
 On the other hand, many cells of the immune system contribute to cancer
immunology, suppressing cancer