PHL 472 Chemical Carcinogens

1
PHL 472 Chemical Carcinogens
Abdelkader Ashour, Ph.D.4th Lecture
2
Classification of Carcinogens According tothe
Mode of Action, Based on Reactivity with DNA

• 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

3
Epigenetic Carcinogens, Mechanisms

• Prolonged stimulation of cell proliferation, via
  chronic cytotoxicity or increased secretion
  trophic hormones
• Inhibition of apoptosis in cells with DNA damage
• Impairment of DNA-replication fidelity and
  DNA-repairing machinery
• Dysregulated gene expression
• Altered DNA methylation status in the genes that
  control cell growth and differentiation
• Induction of metabolizing enzymes
• Dysregulated cell signaling via receptor- or
  non-receptor-mediated pathways
• Persistent immunosuppression, leading to
  compromised immunosurveillance
• Oxidative Stress
• Indirect DNA damage
• Induction of cell proliferation signaling cascades

4
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

5
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

6
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

7
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

8
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

9
Kinase-linked Receptors, Activation of Ras
following binding of a hormone (e.g., EGF) to an
RTK.

• The adapter protein GRB2 binds to a specific
  phosphotyrosine on the activated RTK and to Sos,
  which in turn interacts with the inactive
  RasGDP.
• The guanine nucleotide exchange factor (GEF)
  activity of Sos then promotes formation of active
  RasGTP.
• Note that Ras is tethered to the membrane by a
  farnesyl anchor

10
Kinase-linked Receptors, Kinase cascade that
transmits signals downstream from activated Ras
protein

• Activated Ras binds to the N-terminal domain of
  Raf, a serine/threonine kinase.
• Raf binds to and phosphorylates MEK, a
  dual-specificity protein kinase that
  phosphorylates both tyrosine and serine residues.
• MEK phosphorylates and activates MAP kinase,
  another serine/threonine kinase.
• MAP kinase phosphorylates many different
  proteins, including nuclear transcription
  factors, that mediate cellular responses.

11
Chemical Carcinogens, Representative Members
12
Modifying Factors in Chemical Carcinogenesis

• 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
• 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.

13
Modifying Factors in Chemical Carcinogenesis

• 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
• Genetic factors They influence some specific
  cancers, this influence is a major one.
  The sorts of genetic involvement which have been
  described are
• Single gene - probably directly involved in
  carcinogenesis. Example retinoblastoma.
• Single gene - predisposes to cancer. Example
  xeroderma pigmentosum, a DNA repair defect
• 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

14
(No Transcript)
15
Modifying Factors in Chemical Carcinogenesis

• Biological behaviors of the chemical carcinogen
• 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
• 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
• Species specificity 2-naphthylamine causes
  bladder cancer in man, dog and hamster, but only
  liver cancer in mouse and no effect in rats.
• 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
• 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

16
Modifying Factors in Chemical Carcinogenesis

• Biological behaviors of the chemical carcinogen
• 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
• 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
• 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

17
Modifying factors in chemical carcinogenesis

• 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

• 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

18
Modifying factors in chemical carcinogenesis

• 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